Heterocyclic compounds as immunomodulators

ABSTRACT

Disclosed are compounds of Formula (I′), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.

FIELD OF THE INVENTION

The present application is concerned with pharmaceutically activecompounds. The disclosure provides compounds as well as theircompositions and methods of use. The compounds modulate PD-1/PD-L1protein/protein interaction and are useful in the treatment of variousdiseases including infectious diseases and cancer.

BACKGROUND OF THE INVENTION

The immune system plays an important role in controlling and eradicatingdiseases such as cancer. However, cancer cells often develop strategiesto evade or to suppress the immune system in order to favor theirgrowth. One such mechanism is altering the expression of co-stimulatoryand co-inhibitory molecules expressed on immune cells (Postow et al, J.Clinical Oncology 2015, 1-9). Blocking the signaling of an inhibitoryimmune checkpoint, such as PD-1, has proven to be a promising andeffective treatment modality.

Programmed cell death-1 (PD-1), also known as CD279, is a cell surfacereceptor expressed on activated T cells, natural killer T cells, Bcells, and macrophages (Greenwald et al, Annu. Rev. Immunol 2005,23:515-548; Okazaki and Honjo, Trends Immunol 2006, (4): 195-201). Itfunctions as an intrinsic negative feedback system to prevent theactivation of T-cells, which in turn reduces autoimmunity and promotesself-tolerance. In addition, PD-1 is also known to play a critical rolein the suppression of antigen-specific T cell response in diseases likecancer and viral infection (Sharpe et al, Nat Immunol 2007 8, 239-245;Postow et al, J. Clinical Oncol 2015, 1-9).

The structure of PD-1 consists of an extracellular immunoglobulinvariable-like domain followed by a transmembrane region and anintracellular domain (Parry et al, Mol Cell Biol 2005, 9543-9553). Theintracellular domain contains two phosphorylation sites located in animmunoreceptor tyrosine-based inhibitory motif and an immunoreceptortyrosine-based switch motif, which suggests that PD-1 negativelyregulates T cell receptor-mediated signals. PD-1 has two ligands, PD-L1and PD-L2 (Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al,Nat Immunol 2001, 2, 261-268), and they differ in their expressionpatterns. PD-L1 protein is upregulated on macrophages and dendriticcells in response to lipopolysaccharide and GM-CSF treatment, and on Tcells and B cells upon T cell receptor and B cell receptor signaling.PD-L1 is also highly expressed on almost all tumor cells, and theexpression is further increased after IFN-γ treatment (Iwai et al, PNAS2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5). Infact, tumor PD-L1 expression status has been shown to be prognostic inmultiple tumor types (Wang et al, Eur J Surg Oncol 2015; Huang et al,Oncol Rep 2015; Sabatier et al, Oncotarget 2015, 6(7): 5449-5464). PD-L2expression, in contrast, is more restricted and is expressed mainly bydendritic cells (Nakae et al, J Immunol 2006, 177:566-73). Ligation ofPD-1 with its ligands PD-L1 and PD-L2 on T cells delivers a signal thatinhibits IL-2 and IFN-γ production, as well as cell proliferationinduced upon T cell receptor activation (Carter et al, Eur J Immunol2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7): 1027-34). Themechanism involves recruitment of SHP-2 or SHP-1 phosphatases to inhibitT cell receptor signaling such as Syk and Lck phosphorylation (Sharpe etal, Nat Immunol 2007, 8, 239-245). Activation of the PD-1 signaling axisalso attenuates PKC-θ activation loop phosphorylation, which isnecessary for the activation of NF-κB and API pathways, and for cytokineproduction such as IL-2, IFN-γ and TNF (Sharpe et al, Nat Immunol 2007,8, 239-245; Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman etal, J Exp Med 2000, 192(7):1027-34).

Several lines of evidence from preclinical animal studies indicate thatPD-1 and its ligands negatively regulate immune responses.PD-1-deficient mice have been shown to develop lupus-likeglomerulonephritis and dilated cardiomyopathy (Nishimura et al, Immunity1999, 11:141-151; Nishimura et al, Science 2001, 291:319-322). Using anLCMV model of chronic infection, it has been shown that PD-1/PD-L1interaction inhibits activation, expansion and acquisition of effectorfunctions of virus-specific CD8 T cells (Barber et al, Nature 2006, 439,682-7). Together, these data support the development of a therapeuticapproach to block the PD-1-mediated inhibitory signaling cascade inorder to augment or “rescue” T cell response. Accordingly, there is aneed for new compounds that block PD-1/PD-L1 protein/proteininteraction.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I′):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinconstituent variables are defined herein.

The present disclosure further provides a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinconstituent variables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, and at least onepharmaceutically acceptable carrier or excipient.

The present disclosure further provides methods of modulating orinhibiting PD-1/PD-L1 protein/protein interaction, which comprisesadministering to an individual a compound of the disclosure, or apharmaceutically acceptable salt or a stereoisomer thereof.

The present disclosure further provides methods of treating a disease ordisorder in a patient comprising administering to the patient atherapeutically effective amount of a compound of the disclosure, or apharmaceutically acceptable salt or a stereoisomer thereof.

DETAILED DESCRIPTION I. Compounds

The present disclosure provides, inter alia, a compound of Formula (I′):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

one of Y¹ and Y² is N and the other of Y¹ and Y² is C;

X¹ is N or CR¹;

X² is N or CR²;

X³ is N or CR³;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

X⁶ is N or CR⁶;

Cy is C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5- to 14-membered heteroaryl, or 4-to 10-membered heterocycloalkyl, each of which is optionally substitutedwith 1 to 4 independently selected R⁷ substituents;

Z¹ is N or CR^(8a);

Z² is N or CR^(8b);

Z³ is N or CR^(8c);

R¹, R², R^(8a), R^(8b) and R^(8c) are each independently selected fromH, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-, C₆₋₁₀ aryl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, CN,OR¹⁰, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NHR¹⁰, —NR¹⁰R¹⁰, NHOR¹⁰,C(O)R¹⁰, C(O)NR¹⁰R¹⁰, C(O)OR¹⁰, OC(O)R¹⁰, OC(O)NR¹⁰R¹⁰, NR¹⁰C(O)R¹⁰,NR¹⁰C(O)OR¹⁰, NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰, C(═NR¹⁰)NR¹⁰R¹⁰,NR¹⁰C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰, NR¹⁰S(O)₂NR¹⁰R¹⁰,S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and S(O)₂NR¹⁰R¹⁰, wherein each R¹⁰ isindependently selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-, C₆₋₁₀ aryl,C₆₋₁₀ aryl-C₁₋₄ alkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄ alkyl-, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R¹, R², R^(8a), R^(8b), R^(8c) and R¹⁰ are each optionallysubstituted with 1, 2 or 3 independently selected R^(b) substituents;

R⁹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR¹¹, —SR¹¹, NH₂, NHR¹¹,—NR¹¹R¹¹, NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹, C(O)OR¹¹, OC(O)R¹¹,OC(O)NR¹¹R¹¹, NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹¹, C(═NR¹¹)R¹¹,C(═NR¹¹)NR¹¹R¹¹, NR¹¹C(═NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹,NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and S(O)₂NR¹¹R¹¹,wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁹ are each optionally substituted with1, 2 or 3 R^(b) substituents;

-   -   each R¹¹ is independently selected from H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered        heteroaryl)-C₁₋₄ alkyl- and (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl- of R¹¹ are each optionally        substituted with 1, 2 or 3 independently selected R^(b)        substituents;

R³, R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵, R⁶ and R⁷ are eachoptionally substituted with 1, 2, 3, or 4 R^(b) substituents, with theproviso that at least one of R³, R⁴, R⁵ and R⁶ is other than H;

or two adjacent R⁷ substituents on the Cy ring, taken together with theatoms to which they are attached, form a fused phenyl ring, a fused 5-,6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-memberedheteroaryl ring or a fused C₃₋₆ cycloalkyl ring, wherein the fused 5-,6- or 7-membered heterocycloalkyl ring and fused 5- or 6-memberedheteroaryl ring each have 1-4 heteroatoms as ring members selected fromN, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(b) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1-3 independently selected R^(h) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each furtheroptionally substituted with 1-3 independently selected R^(d)substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR)NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o);

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1-3 R^(p) substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(r), OR^(r), SR^(r),C(O)R^(r), C(O)NR^(r)R^(r), C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r),NHR^(r), NR^(r)R^(r), NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r),NR^(r)C(O)OR^(r), C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r)and S(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionallysubstituted with 1, 2 or 3 R^(q) substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3 R^(j)substituents independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k),SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents; ortwo R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; and

each R^(e), R^(i), R^(k), R^(o) or R^(p) is independently selected fromH, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,4-7 membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl of R^(e), R^(i), R^(k), R^(o) or R^(p) are each optionallysubstituted with 1, 2 or 3 R^(q) substituents;

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR¹²,NR¹²R¹², and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroarylof R^(q) are each optionally substituted with halo, OH, CN, —COOH, NH₂,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyland each R¹² is independently C₁₋₆ alkyl;

is a single bond or a double bond to maintain ring A being aromatic; and

with the proviso that the compound is other than6-(6-chloro-3-methylimidazol[1,2-a]pyridine-2-yl)-4-(4-chlorophenyl)-(1,1-dimethylethoxy)-2,5-dimethyl-3-pyridineaceticacid or6-(6-chloroimidazol[1,2-a]pyridine-2-yl)-4-(4-chlorophenyl)-(1,1-dimethylethoxy)-2,5-dimethyl-3-pyridineaceticacid, or enantiomers thereof.

The present disclosure provides a compound of Formula (I′), or apharmaceutically acceptable salt or a stereoisomer thereof, wherein:

one of Y¹ and Y² is N and the other of Y¹ and Y² is C;

X¹ is N or CR¹;

X² is N or CR²;

X³ is N or CR³;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

X⁶ is N or CR⁶;

Cy is C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5- to 14-membered heteroaryl, or 4-to 10-membered heterocycloalkyl, each of which is optionally substitutedwith 1 to 4 independently selected R⁷ substituents;

Z¹ is N or CR^(8a);

Z² is N or CR^(8b);

Z³ is N or CR^(8c);

R¹, R², R^(8a), R^(8b) and R^(8c) are each independently selected fromH, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, CN,OH, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl,—N(C₁₋₄ alkyl)₂, NHOR¹⁰, C(O)R¹⁰, C(O)NR¹⁰R¹⁰, C(O)OR¹⁰, OC(O)R¹⁰,OC(O)NR¹⁰R¹⁰, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)OR¹⁰, NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰,C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰,NR¹⁰S(O)₂NR¹⁰R¹⁰, S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and S(O)₂NR¹⁰R¹⁰,wherein each R¹⁰ is independently selected from H and C₁₋₄ alkyloptionally substituted with 1 or 2 groups independently selected fromhalo, OH, CN and C₁₋₄ alkoxy; and wherein the C₁₋₄ alkyl, C₃₋₄cycloalkyl, C₂₋₄ alkenyl and C₂₋₄ alkynyl of R¹, R², R^(8a), R^(8b), orR^(8c) are each optionally substituted with 1 or 2 substituentsindependently selected from halo, OH, CN and C₁₋₄ alkoxy;

R⁹ is C₁₋₄ alkyl, halo, CN, OH, cyclopropyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂,NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹, C(O)OR¹¹, OC(O)R¹¹, OC(O)NR¹¹R¹¹,NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹¹, C(═NR¹¹)R¹¹,C(═NR¹¹)NR¹¹R¹¹, NR¹¹C(═NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹,NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and S(O)₂NR¹¹R¹¹,wherein C₁₋₄ alkyl, cyclopropyl, C₂₋₄ alkynyl and C₁₋₄ alkoxy of R⁹ areeach optionally substituted with 1 or 2 substituents selected from halo,OH, CN and OCH₃ and each R¹¹ is independently selected from H and C₁₋₄alkyl optionally substituted with 1 or 2 halo, OH, CN or OCH₃substituents;

R³, R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵, R⁶ and R⁷ are eachoptionally substituted with 1, 2, 3, or 4 R^(b) substituents, with theproviso that at least one of R³, R⁴, R⁵ and R⁶ is other than H;

or two adjacent R⁷ substituents on the Cy ring, taken together with theatoms to which they are attached, form a fused phenyl ring, a fused 5-,6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-memberedheteroaryl ring or a fused C₃₋₆ cycloalkyl ring, wherein the fused 5-,6- or 7-membered heterocycloalkyl ring and fused 5- or 6-memberedheteroaryl ring each have 1-4 heteroatoms as ring members selected fromN, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(b) substituents or 1, 2 or 3 independentlyselected R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH₂,NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl ofR^(d) are each further optionally substituted with 1-3 independentlyselected R^(q) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each furtheroptionally substituted with 1-3 independently selected R^(d)substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR)NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR)NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o);

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1-3 independently selected R^(p)substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-,(4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i),NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i),and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each furtheroptionally substituted by 1, 2, or 3 R^(j) substituents independentlyselected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k); or twoR^(h) groups attached to the same carbon atom of the 4- to 10-memberedheterocycloalkyl taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkylhaving 1-2 heteroatoms as ring members selected from O, N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; and

each R^(e), R^(i), R^(k), R^(o) or R^(p) is independently selected fromH, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl of R^(e), R^(i), R^(k), R^(o) or R^(p) are eachoptionally substituted with 1, 2 or 3 R^(q) substituents;

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylthio,phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl,phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl of R^(q) are each optionally substituted with halo, OH, CN,—COOH, NH₂, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀cycloalkyl and 4-6 membered heterocycloalkyl and each R¹² isindependently C₁₋₆ alkyl; and

is a single bond or a double bond to maintain ring A being aromatic.

In some embodiments of compounds of Formula (I′), Cy is C₆₋₁₀ aryl,optionally substituted with 1 to 4 independently selected R⁷substituents. In certain embodiments, Cy is phenyl or naphthyl, each ofwhich is optionally substituted with 1 to 4 independently selected R⁷substituents. In certain embodiments, Cy is phenyl optionallysubstituted with 1 to 4 independently selected R⁷ substituents. Incertain embodiments, Cy is unsubstituted phenyl.

In some embodiments of compounds of Formula (I′), Cy is C₃₋₁₀cycloalkyl, optionally substituted with 1 to 4 independently selected R⁷substituents. In certain embodiments, Cy is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, eachof which is optionally substituted with 1 to 4 independently selected R⁷substituents.

In some embodiments of compounds of Formula (I′), Cy is 5- to14-membered heteroaryl, optionally substituted with 1 to 4 independentlyselected R⁷ substituents. In certain embodiments, Cy is pyridy,primidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl,azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl,quinolinyl, isoquinolinyl, naphthyridinyl, indolyl, benzothiophenyl,benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, thienyl,furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl, each of which is optionallysubstituted with 1 to 4 independently selected R⁷ substituents.

In some embodiments of compounds of Formula (I′), Cy is 4- to10-membered heterocycloalkyl, optionally substituted with 1 to 4independently selected R⁷ substituents. In certain embodiments, Cy isazetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl,dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl,pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl,2,3-dihydro-1,4-benzodioxin-6-yl, and thiomorpholino, each of which isoptionally substituted with 1 to 4 independently selected R⁷substituents. In some embodiments, Cy is 3-dihydro-1,4-benzodioxin-6-yloptionally substituted with 1 to 4 independently selected R⁷substituents.

In some embodiments of compounds of Formula (I′), Z¹ is CR^(8a), Z² isCR^(8b) and Z³ is CR^(8c). In certain instances, R^(8a), R^(8b) andR^(8c) are each H.

In some embodiments of compounds of Formula (I′), Z¹ is CR^(8a), Z² is Nand Z³ is N. In certain instances, R^(8a) is H.

In some embodiments of compounds of Formula (I′), Z¹ is CR^(8a), Z² is Nand Z³ is CR^(8c). In certain instances, R^(8a) and R^(8c) are each H.

In some embodiments of compounds of Formula (I′), Z¹ is CR^(8a), Z² isCR^(8b) and Z³ is N. In certain instances, R^(8a) and R^(8b) are each H.

In some embodiments of compounds of Formula (I′), Z¹ is N, Z² is CR^(8b)and Z³ is CR^(8c). In certain instances, R^(8b) and R^(8c) are each H.

In some embodiments of compounds of Formula (I′), Z¹ is N, Z² is N andZ³ is CR^(8c). In certain instances, R^(8c) is H.

In some embodiments of compounds of Formula (I′), Z¹ is N, Z² is CR^(8b)and Z³ is N. In certain instances, R^(8b) is H.

In some embodiments of compounds of Formula (I′), Z¹, Z² and Z³ are eachN.

In some embodiments, the present disclosure provides compounds ofFormula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

one of Y¹ and Y² is N and the other of Y¹ and Y² is C;

X¹ is N or CR¹;

X² is N or CR²;

X³ is N or CR³;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

X⁶ is N or CR⁶;

R¹, R² and R⁸ are each independently selected from H, C₁₋₄ alkyl, C₃₄cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, CN, OH, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂,NHOR¹⁰, C(O)R¹⁰, C(O)NR¹⁰R¹⁰, C(O)OR¹⁰, OC(O)R¹⁰, OC(O)NR¹⁰R¹⁰,NR¹⁰C(O)R¹⁰, NR¹⁰C(O)OR¹⁰, NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰,C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰,NR¹⁰S(O)₂NR¹⁰R¹⁰, S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and S(O)₂NR¹⁰R¹⁰,wherein each R¹⁰ is independently H or C₁₋₄ alkyl optionally substitutedwith 1 or 2 groups independently selected from halo, OH, CN and C₁₋₄alkoxy and the C₁₋₄ alkyl, C₃₋₄ cycloalkyl, C₂₋₄ alkenyl and C₂₋₄alkynyl of R¹, R² or R⁸ are each optionally substituted with 1 or 2substituents independently selected from halo, OH, CN and C₁₋₄ alkoxy;

R⁹ is C₁₋₄ alkyl, halo, CN, OH, cyclopropyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂,NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹, C(O)OR¹¹, OC(O)R¹¹, OC(O)NR¹¹R¹¹,NR¹¹C(O)R¹¹, —NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹¹, C(═NR¹¹)R¹¹,C(═NR¹¹)NR¹¹R¹¹, NR¹¹C(═NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹,NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and S(O)₂NR¹¹R¹¹,wherein each R¹¹ is independently H or C₁₋₄ alkyl optionally substitutedwith 1 or 2 halo, OH, CN or OCH₃;

R³, R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵, R⁶ and R⁷ are eachoptionally substituted with 1, 2, 3, or 4 R^(b) substituents, with theproviso that at least one of R³, R⁴, R⁵ and R⁶ is other than H;

or two adjacent R⁷ substituents on the phenyl ring, taken together withthe carbon atoms to which they are attached, form a fused phenyl ring, afused 5- or 6-membered heterocycloalkyl ring, a fused 5- or 6-memberedheteroaryl ring or a fused C₅₋₆ cycloalkyl ring, wherein the fused 5- or6-membered heterocycloalkyl ring and fused 5- or 6-membered heteroarylring each have 1-4 heteroatoms as ring members selected from N, O and Sand wherein the fused phenyl ring, fused 5- or 6-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₅₋₆ cycloalkyl ring are each optionally substituted with 1 or 2independently selected R^(q) substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH₂,NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl ofR^(d) are each further optionally substituted with 1-3 independentlyselected R^(q) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) or S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each furtheroptionally substituted with 1-3 independently selected R^(d)substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g),OR^(g), SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR)NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR)NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o);

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1-3 independently selected R^(p)substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-,(4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i),NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i),and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each furtheroptionally substituted by 1, 2, or 3 R^(j) substituents independentlyselected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k); or twoR^(h) groups attached to the same carbon atom of the 4- to 10-memberedheterocycloalkyl taken together with the carbon atom to which theyattach form a C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkylhaving 1-2 heteroatoms as ring members selected from O, N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; and

each R^(e), R^(i), R^(k), R^(o) or R^(p) is independently selected fromH, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl of R^(e), R^(i), R^(k), R^(o) or R^(p) are eachoptionally substituted with 1, 2 or 3 R^(q) substituents;

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, phenyl, 5-6 membered heteroaryl,C₃₋₆ cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄ haloalkoxy, wherein the C₁₋₄alkyl, phenyl and 5-6 membered heteroaryl of R^(q) are each optionallysubstituted with OH, CN, —COOH, NH₂, C₁₋₄ alkoxy, C₃₋₁₀ cycloalkyl and4-6 membered heterocycloalkyl and each R¹² is independently C₁₋₆ alkyl;

is a single bond or a double bond to maintain ring A being aromatic;

the subscript n is an integer of 1, 2, 3, 4 or 5; and

the subscript m is an integer of 1, 2, 3 or 4. In some embodiments, thesubscript m is an integer of 1, 2 or 3.

In some embodiments, R⁹ is C₁₋₄ alkyl, halo, CN, OH, cyclopropyl, C₂₋₄alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄alkyl, —N(C₁₋₄ alkyl)₂, NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹, C(O)OR¹¹,OC(O)R¹¹, OC(O)NR¹¹R¹¹, NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹¹,C(═NR¹¹)R¹¹, C(═NR¹¹)NR¹¹R¹¹, NR¹¹C(═NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹,NR¹¹S(O)₂R¹¹, NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, andS(O)₂NR¹¹R¹¹, wherein C₁₋₄ alkyl, cyclopropyl, C₂₋₄ alkynyl and C₁₋₄alkoxy of R⁹ are each optionally substituted with 1 or 2 substituentsselected from halo, OH, CN and OCH₃ and each R¹¹ is independently H orC₁₋₄ alkyl optionally substituted with 1 or 2 halo, OH, CN or OCH₃.

In some embodiments, two adjacent R⁷ substituents on the phenyl ring,taken together with the carbon atoms to which they are attached, form afused phenyl ring, a fused 5- or 6-membered heterocycloalkyl ring, afused 5- or 6-membered heteroaryl ring or a fused C₅₋₆ cycloalkyl ring,wherein the fused 5- or 6-membered heterocycloalkyl ring and fused 5- or6-membered heteroaryl ring each have 1-4 heteroatoms as ring membersselected from N, O and S and wherein the fused phenyl ring, fused 5- or6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ringand fused C₅₋₆ cycloalkyl ring are each optionally substituted with 1, 2or 3 independently selected R^(b) substituents or 1 or 2 independentlyselected R^(q) substituents. The compounds, or pharmaceuticallyacceptable salts or stereoisomers thereof, as described herein areuseful as inhibitors of the PD-1/PD-L1 protein/protein interaction. Forexample, compounds or pharmaceutically acceptable salts or stereoisomersthereof as described herein can disrupt the PD-1/PD-L1 protein/proteininteraction in the PD-1 pathway.

In some embodiments, the present disclosure provides compounds havingFormula (II):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinR⁴ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R¹ are each optionally substituted with1, 2, 3, or 4 R^(b) substituents. Other variables of Formula (II) are asdefined in Formula (I′) or (I) or any embodiment of compounds of Formula(I′) or (I) as described herein. In one embodiment of compounds ofFormula (II), R⁹ is CN or C₁₋₄ alkyl optionally substituted with R^(q).In another embodiment, R⁹ is CH₃ or CN.

In some embodiments, the present disclosure provides compounds havingFormula (IIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinR⁵ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R¹ are each optionally substituted with1, 2, 3, or 4 R^(b) substituents. Other variables of Formula (IIa) areas defined in Formula (I′) or (I) or any embodiment of compounds ofFormula (I) as described herein. In one embodiment of compounds ofFormula (II), R⁹ is CN or C₁₋₄ alkyl optionally substituted with R^(q).In another embodiment, R⁹ is CH₃ or CN.

In some embodiments, the present disclosure provides compounds havingFormula (III):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (III) are as defined in Formula (I′) or (I) orany embodiment of compounds of Formula (I′) or (I) as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (IV):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (IV) are as defined in Formula (I′) or (I) orany embodiment of compounds of Formula (I′) or (I) as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (V):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (V) are as defined in Formula (I′) or (I) orany embodiment of compounds of Formula (I′) or (I) as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (VI):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (VI) are as defined in Formula (I′) or (I) orany embodiment of compounds of Formula (I′) or (I) as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (VII):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (VII) are as defined in Formula (I′) or (I) orany embodiment of compounds of Formula (I′) or (I) as described herein.In some instances, R⁷ is H, n is 1, Z¹ is CR^(8a), Z² is CR^(8b) and Z³is CR^(8c). In certain instances, Z¹, Z² and Z³ are each H.

In some embodiments, the present disclosure provides compounds havingFormula (VIII):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (VIII) are as defined in Formula (I′) or (I) orany embodiment of compounds of Formula (I′) or (I) as described herein.In some instances, R⁷ is H, n is 1, Z¹ is CR^(8a), Z² is CR^(8b) and Z³is CR^(8c). In certain instances, Z¹, Z² and Z³ are each H.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, or a pharmaceutically acceptable salt or astereoisomer thereof, the moiety:

is selected from:

wherein the substituents R¹, R², R³, R⁴, R⁵ and R⁶ are as defined inFormula (I′) or (I) or any embodiment of compounds of Formula (I′) or(I) as described herein. In certain embodiments, at each occurrence, R¹,R², R³ and R⁵ are each H.

In some embodiments, the moiety:

is selected from:

wherein the substituents R¹, R², R³, R⁴, R⁵ and R⁶ are as defined inFormula (I′) or (I) or any embodiment of compounds of Formula (I′) or(I) as described herein. In certain embodiments, at each occurrence, R¹,R², R³ and R⁵ are each H.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X¹ is N, X² is CH, X³, X⁵ and X⁶ are each CH, Y¹ is Nand Y² is C.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X¹ is CH, X² is CH, X³, X⁵ and X⁶ are each CH, Y¹ is Cand Y² is N.

In some embodiments of compounds of Formula I′, I, II, III, IV, V, VI,or VII, X¹ is CH, X² is CH, X³ and X⁶ are each CH, X⁵ is N, Y¹ is C andY² is N.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X¹ is N, X² is CH, X³ and X⁶ are each N, X⁵ is CH, Y¹is N and Y² is C.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X¹ is N, X² is CH, X³ and X⁵ are each CH, X⁶ is N, Y¹is N and Y² is C.

In some embodiments of compounds of Formula I′, I, II, III, IV, V, VI,or VII, X¹ is N, X² is CH, X³ and X⁶ are each CH, X⁵ is N, Y¹ is N andY² is C.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X¹ is N, X² is CH, X⁵ and X⁶ are each CH, X³ is N, Y¹is N and Y² is C.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X¹ and X² are each N, X³, X⁵ and X⁶ are each CH, Y¹ isC and Y² is N.

In some embodiments of compounds of Formula I′, I, II, III, IV, V, VI,or VII, X¹ and X² are each N, X³ is CH, X⁵ is N, X⁶ is CR⁶, Y¹ is C andY² is N.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X¹ is N, X² is CH, X³ and X⁵ are each CH, X⁶ is CR⁶,Y¹ is N and Y² is C.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,or VI, VII, or VIII, X¹ and X² are each N, X³ and X⁵ are each CH, X⁶ isCR⁶, Y¹ is N and Y² is C.

In some embodiments, R⁹ is C₁₋₄ alkyl or CN.

In some embodiments, R⁹ is CH₃ or CN.

In some embodiments, R⁷ and R⁸ are each H.

In some embodiments, R^(8a), R^(8b), and R^(8c) are each H.

In some embodiments, R⁷, R^(8a), R^(8b), and R^(8c) are each H.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X², X³, X⁵ and X⁶ are each CH.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X¹, X², X³, X⁵ and X⁶ are each CH.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X¹, X², X³ and X⁶ are each CH.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X² and X⁵ are each CH.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X², X³ and X⁵ are each CH.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X² and X⁶ are each CH.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X², X⁵ and X⁶ are each CH.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X³, X⁵ and X⁶ are each CH.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, X³ is CH.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, R⁴ is C₁₋₄ alkyl substituted with R^(b). In certainembodiments, R^(b) is NHR^(c) or NR^(c)R^(c). In other embodiments,R^(b) is 2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino,2-carboxypiperidin-1-yl, (cyanomethyl)amino,(S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or2-carboxypiperidin-1-yl. In other embodiments, R⁴ is C₁₋₄ alkylsubstituted with R^(d). In other embodiments, R⁴ is C₁₋₄ alkylsubstituted with R^(f). In other embodiments, R⁴ is C₁₋₄ alkylsubstituted with R^(h). In other embodiments, R⁴ is C₁₋₄ alkylsubstituted with R. In other embodiments, R⁴ is C₁₋₄ alkyl substitutedwith R^(n). In other embodiments, R⁴ is C₁₋₄ alkyl substituted withR^(q).

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, R⁴ is —CH₂R^(b). In certain embodiments, R^(b) isNHR^(c) or NR^(c)R^(c). In other embodiments, R^(b) is2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino,2-carboxypiperidin-1-yl, (cyanomethyl)amino,(S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or2-carboxypiperidin-1-yl. In other embodiments, R⁴ is —CH₂—R^(d). Inother embodiments, R⁴ is —CH₂—R^(f). In other embodiments, R⁴ is—CH₂—R^(h). In other embodiments, R⁴ is —CH₂—R^(j). In otherembodiments, R⁴ is —CH₂—R^(n). In other embodiments, R⁴ is —CH₂—R^(q).

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, R⁴ is 2-hydroxyethylaminomethyl,2-hydroxyethyl(methyl)aminomethyl, 2-carboxypiperidin-1-ylmethyl,(cyanomethyl)aminomethyl, (S)-2-carboxypiperidin-1-ylmethyl,(R)-2-carboxypiperidin-1-ylmethyl or 2-carboxypiperidin-1-ylmethyl.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, R⁶ is H, halo or C₁₋₆ alkyl optionally substitutedwith 1-3 R^(q) substituents.

In some embodiments of compounds of Formula I′, I, II, IIa, III, IV, V,VI, VII, or VIII, R⁶ is H, halo or CH₃.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds offormula (I′) or (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)-includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m)alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “amino” refers to a group of formula —NH₂.

The term “carbamyl” refers to a group of formula —C(O)NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m)haloalkyl” refers to a C-m alkyl group having n to mcarbon atoms and from at least one up to {2(n to m)+1}halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments, thehaloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, indanyl, indenyl and the like. In someembodiments, aryl groups have from 6 to about 10 carbon atoms. In someembodiments aryl groups have 6 carbon atoms. In some embodiments arylgroups have 10 carbon atoms. In some embodiments, the aryl group isphenyl. In some embodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridintl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl,quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-,1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine), indolyl,benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl,purinyl, and the like.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur oxygen and phosphorus, and which has 4-10ring members, 4-7 ring members, or 4-6 ring members. Included within theterm “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orbicyclic (e.g., having two fused or bridged rings) ring systems. In someembodiments, the heterocycloalkyl group is a monocyclic group having 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur andoxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkylgroup can be optionally oxidized to form an oxo or sulfido group orother oxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, N-oxide etc.)or a nitrogen atom can be quaternized. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the heterocycloalkyl ring, e.g.,benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. Examples of heterocycloalkyl groups include azetidinyl,azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl,morpholino, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl,pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, andthiomorpholino.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as 3-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups inOrganic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of formula (I′) or (I) can be prepared, e.g., using a processas illustrated in Schemes 1-5.

The compounds of Formula 4 can be prepared according to Scheme 1. Thehalo group (e.g., Hal^(I)=Cl, Br, I) of biphenyl compounds 1 can beconverted to the boronic esters 2 under standard conditions [e.g., inthe presence of bis(pinacolato)diboron and a palladium catalyst, suchas, tetrakis(triphenylphosphine) palladium(0), palladium(II) acetate].Boronates 2 can react with the heteroaryl halides 3 (e.g., Hal²=Cl, Br,I) under standard Suzuki coupling condition (e.g., in the presence of apalladium catalyst and a suitable base) to give the N-bridged bicycliccompounds 4.

The N-bridged heteroaryl compounds of Formula 10 can also be preparedaccording to Scheme 2. Briefly, the halo group of the substituted phenylethanone 5 (e.g., Hal³=Cl, Br or I) can be coupled with substitutedphenyl boronic esters 6 under standard Suzuki coupling condition (e.g.,in the presence of a palladium catalyst and a suitable base) to producethe biphenyl compounds 7. Bromination of the methyl ketones 7 usingbrominating reagents including, but not limited, to copper(II) bromidecan generate α-bromo ketones 8. Condensation of α-bromo ketones 8 andamino heterocycles 9 in polar solvents (e.g., isopropanol) under heatingcan afford the N-bridged heteroaryl compounds 10.

The triazole-containing heteroaryl halides of formula 13 (Hal⁴ is ahalide such as Br or I) can be formed according to Scheme 3. Coupling ofamino heterocycles 9 with ethoxycarbonyl isothiocyanate 11, followed bytreatment with hydroxylamine hydrochloride and diisopropylethylamine(DIPEA) can form N-bridged heteroaryl amines 12. Conversion of theprimary amine in 12 to halides can be achieved under Sandmeyer reactionconditions [i.e. in the presence of tert-butyl nitrite and a halogensources such as CuBr₂ or I₂] to generate the N-bridged heteraryl halides13.

The N-bridged heteroaryl compounds of Formula 18 can be preparedaccording to Scheme 4, starting from compounds of formula 14 or 15 whichcan be prepared according to procedures as described in Scheme 1 or 2.Heteroaryl esters 14 can be reduced to aldehydes 16 via a sequence ofreduction (e.g., LiAlH₄ or LiBH₄ as reducing reagents) and oxidation(e.g., Dess-Martin periodinane as oxidant). The aldehydes 16 might alsobe formed via direct reduction of esters 14 under mild reducingconditions [e.g., using diisobutylaluminium hydride (DIBAL) as thereducing agent at low temperature]. Alternatively, aldehydes 16 can beformed through a direct reduction of nitriles 15 with DIBAL as thereducing reagent at low temperature. Then the aldehydes 16 can reactwith amines 17 of formula HNR^(c)R^(c) under standard reductiveamination conditions (e.g., sodium triacetoxyborohydride or sodiumcyanoborohydride as reducing reagents) to generate compounds of formula18.

Alternatively, aldehydes 16 can also be prepared using procedures asshown in Scheme 5, starting from heteroaryl halides 19 (e.g., Hal⁵=Cl,Br, I) which can be synthesized according to procedures as described inScheme 1 or 2. The halide in compounds 19 can be converted to vinylgroup to give olefins 20, under standard Suzuki coupling condition(e.g., with vinylboronic acid pinaco ester in the presence of apalladium catalyst and a suitable base). The vinyl group in compounds 20can be oxidatively cleaved by NaIO₄ in the presence of catalytic amountof OsO₄ to form aldehydes 16.

Compounds of Formula 25 can be prepared using procedures as outlined inScheme 6. The halo group (e.g., Hal²=Cl, Br, I) of heteroaryl compounds3 can be converted to the boronic esters 21 under standard conditions[e.g., in the presence of bis(pinacolato)diboron and a palladiumcatalyst, such as, tetrakis(triphenylphosphine) palladium(0),palladium(II) acetate]. Selective coupling of boronates 21 with arylhalides 22 (e.g., Hal⁶=Cl, Br, I) under suitable Suzuki couplingcondition (e.g., in the presence of a palladium catalyst and a suitablebase) can give the N-bridged bicyclic compounds 23. The halide (e.g.,Hal⁷=Cl, Br, I) in compound 23 can be coupled to compounds of formula24, in which M is a boronic acid, boronic ester or an appropriatelysubstituted metal [e.g., M is B(OR)₂, Sn(Alkyl)₄, or Zn-Hal], underSuzuki coupling conditions (e.g., in the presence of a palladiumcatalyst and a suitable base) or Stille coupling conditions (e.g., inthe presence of a palladium catalyst), or Negishi coupling conditions(e.g., in the presence of a palladium catalyst) to give derivatives ofFormula 25. Alternatively, compound 24 can be a cyclic amine (where M isH and attached to an amine nitrogen in ring Cy) and the coupling of arylhalide 23 with the cyclic amine 24 can be performed under Buchwaldamination conditions (e.g., in the presence of a palladium catalyst anda base such as sodium tert-butoxide).

Alternatively, Compounds of Formula 25 can be prepared using theprocedures as outlined in Scheme 7. Selective coupling of aryl halides26 with compounds of formula 24 [M is a boronic acid, boronic ester oran appropriately substituted metal, e.g., M is B(OR)₂, Sn(Alkyl)₄, orZn-Hal] can be achieved under suitable Suzuki coupling, Stille couplingor Negishi coupling conditions to give compounds of Formula 27. Ifcompound 24 is a cyclic amine (e.g., M is H and attached to nitrogen inring Cy), the coupling can be achieved under Buchwald aminationconditions. Conversion of compound 27 to the final product 25 can beachieved using similar conditions as described in Scheme 1.

III. Uses of the Compounds

Compounds of the present disclosure can inhibit the activity ofPD-1/PD-L1 protein/protein interaction and, thus, are useful in treatingdiseases and disorders associated with activity of PD-1 and the diseasesand disorders associated with PD-L1 including its interaction with otherproteins such as PD-1 and B7-1 (CD80). In certain embodiments, thecompounds of the present disclosure, or pharmaceutically acceptablesalts or stereoisomers thereof, are useful for therapeuticadministration to enhance immunity in cancer or chronic infection,including enhancement of response to vaccination. In some embodiments,the present disclosure provides a method for inhibiting the PD-1/PD-L1protein/protein interaction. The method includes administering to anindividual or a patient a compound of Formula (I′) or (I) or of any ofthe formulas as described herein, or of a compound as recited in any ofthe claims and described herein, or a pharmaceutically acceptable saltor a stereoisomer thereof. The compounds of the present disclosure canbe used alone, in combination with other agents or therapies or as anadjuvant or neoadjuvant for the treatment of diseases or disorders,including cancer or infection diseases. For the uses described herein,any of the compounds of the disclosure, including any of the embodimentsthereof, may be used.

The compounds of the present disclosure inhibit the PD-1/PD-L1protein/protein interaction, resulting in a PD-1 pathway blockade. Theblockade of PD-1 can enhance the immune response to cancerous cells andinfectious diseases in mammals, including humans. In some embodiments,the present disclosure provides treatment of an individual or a patientin vivo using a compound of Formula (I′) or (I) or a salt orstereoisomer thereof such that growth of cancerous tumors is inhibited.A compound of Formula (I′) or (I) or of any of the formulas as describedherein, or a compound as recited in any of the claims and describedherein, or a salt or stereoisomer thereof, can be used to inhibit thegrowth of cancerous tumors. Alternatively, a compound of Formula (I′) or(I) or of any of the formulas as described herein, or a compound asrecited in any of the claims and described herein, or a salt orstereoisomer thereof, can be used in conjunction with other agents orstandard cancer treatments, as described below. In one embodiment, thepresent disclosure provides a method for inhibiting growth of tumorcells in vitro. The method includes contacting the tumor cells in vitrowith a compound of Formula (I′) or (I) or of any of the formulas asdescribed herein, or of a compound as recited in any of the claims anddescribed herein, or of a salt or stereoisomer thereof. In anotherembodiment, the present disclosure provides a method for inhibitinggrowth of tumor cells in an individual or a patient. The method includesadministering to the individual or patient in need thereof atherapeutically effective amount of a compound of Formula (I′) or (I) orof any of the formulas as described herein, or of a compound as recitedin any of the claims and described herein, or a salt or a stereoisomerthereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I′) or (I) orany of the formulas as described herein, a compound as recited in any ofthe claims and described herein, or a salt thereof. Examples of cancersinclude those whose growth may be inhibited using compounds of thedisclosure and cancers typically responsive to immunotherapy.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers, especiallymetastatic cancers that express PD-L1.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, colon cancer andlung cancer (e.g. non-small cell lung cancer). Additionally, thedisclosure includes refractory or recurrent malignancies whose growthmay be inhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

PD-1 pathway blockade with compounds of the present disclosure can alsobe used for treating infections such as viral, bacteria fungus andparasite infections. The present disclosure provides a method fortreating infections such as viral infections. The method includesadministering to a patient in need thereof, a therapeutically effectiveamount of a compound of Formula (I′) or (I) or any of the formulas asdescribed herein, a compound as recited in any of the claims anddescribed herein, a salt thereof. Examples of viruses causing infectionstreatable by methods of the present disclosure include, but are notlimit to, human immunodeficiency virus, human papillomavirus, influenza,hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplexviruses, human cytomegalovirus, severe acute respiratory syndrome virus,ebola virus, and measles virus. In some embodiments, viruses causinginfections treatable by methods of the present disclosure include, butare not limit to, hepatitis (A, B, or C), herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus,influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus,comovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measlesvirus, rubella virus, parvovirus, vaccinia virus, HTLV virus, denguevirus, papillomavirus, molluscum virus, poliovirus, rabies virus, JCvirus and arboviral encephalitis virus.

The present disclosure provides a method for treating bacterialinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula(I′) or (I) or any of the formulas as described herein, a compound asrecited in any of the claims and described herein, or a salt thereof.Non-limiting examples of pathogenic bacteria causing infectionstreatable by methods of the disclosure include chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

The present disclosure provides a method for treating fungus infections.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I′) or (I) orany of the formulas as described herein, a compound as recited in any ofthe claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic fungi causing infections treatable by methods ofthe disclosure include Candida (albicans, krusei, glabrata, tropicalis,etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.),Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii,Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioidesimmitis and Histoplasma capsulatum.

The present disclosure provides a method for treating parasiteinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula(I′) or (I) or any of the formulas as described herein, a compound asrecited in any of the claims and described herein, or a salt thereof.Non-limiting examples of pathogenic parasites causing infectionstreatable by methods of the disclosure include Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors for the treatmentof diseases, such as cancer or infections. Examples of cancers includesolid tumors and liquid tumors, such as blood cancers. Examples ofinfections include viral infections, bacterial infections, fungusinfections or parasite infections. For example, the compounds of thepresent disclosure can be combined with one or more inhibitors of thefollowing kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR,PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR,EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT,FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer or infections. Non-limiting examples ofinhibitors that can be combined with the compounds of the presentdisclosure for treatment of cancer and infections include an FGFRinhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 andINCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib,baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat andNLG919), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor, a PI3K-gamma inhibitor such asPI3K-gamma selective inhibitor (e.g., INCB50797), a Pim inhibitor, aCSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer),an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo andextra terminal family members inhibitors (for example, bromodomaininhibitors or BET inhibitors such as INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors. Exemplary immune checkpointinhibitors include inhibitors against immune checkpoint molecules suchas CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK,PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1and PD-L2. In some embodiments, the immune checkpoint molecule is astimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In someembodiments, the compounds provided herein can be used in combinationwith one or more agents selected from KIR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab. In some embodiments, the anti PD-1 antibody isSHR-1210.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518 or MK-4166.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562. Insome embodiments, the OX40L fusion protein is MEDI6383.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM).

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, oncolytic virotherapy and immunomodulating small molecules,including thalidomide or JAK1/2 inhibitor and the like. The compoundscan be administered in combination with one or more anti-cancer drugs,such as a chemotherapeutics. Example chemotherapeutics include any of:abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine,bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi, bortezomib,busulfan intravenous, busulfan oral, calusterone, capecitabine,carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine,clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin,dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin,denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat andzoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab), 4-1BB, antibodies to PD-1 and PD-L1, orantibodies to cytokines (IL-10, TGF-3, etc.). Examples of antibodies toPD-1 and/or PD-L1 that can be combined with compounds of the presentdisclosure for the treatment of cancer or infections such as viral,bacteria, fungus and parasite infections include, but are not limitedto, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The compounds of Formula (I′) or (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or salts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I′) or (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or salts thereof can be used in combination with a vaccination protocolfor the treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I′) or (I) or any of theformulas as described herein, a compound as recited in any of the claimsand described herein, or salts thereof can be combined with dendriticcells immunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

The compounds of Formula (I′) or (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or salts thereof can be used in combination with vaccines, to stimulatethe immune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, comovirus, respiratory syncytialvirus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus,vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscumvirus, poliovirus, rabies virus, JC virus and arboviral encephalitisvirus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I′) or (I) or any of the formulas asdescribed herein, a compound as recited in any of the claims anddescribed herein, or a pharmaceutically acceptable salt thereof, or anyof the embodiments thereof, and at least one pharmaceutically acceptablecarrier or excipient. These compositions can be prepared in a mannerwell known in the pharmaceutical art, and can be administered by avariety of routes, depending upon whether local or systemic treatment isindicated and upon the area to be treated. Administration may be topical(including transdermal, epidermal, ophthalmic and to mucous membranesincluding intranasal, vaginal and rectal delivery), pulmonary (e.g., byinhalation or insufflation of powders or aerosols, including bynebulizer; intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

V. Labeled Compounds and Assay Methods

The compounds of the present disclosure can further be useful ininvestigations of biological processes in normal and abnormal tissues.Thus, another aspect of the present invention relates to labeledcompounds of the invention (radio-labeled, fluorescent-labeled, etc.)that would be useful not only in imaging techniques but also in assays,both in vitro and in vivo, for localizing and quantitating PD-1 or PD-L1protein in tissue samples, including human, and for identifying PD-L1ligands by inhibition binding of a labeled compound. Accordingly, thepresent invention includes PD-1/PD-L1 binding assays that contain suchlabeled compounds.

The present invention further includes isotopically-substitutedcompounds of the disclosure. An “isotopically-substituted” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). It is to be understood that a “radio-labeled”compound is a compound that has incorporated at least one isotope thatis radioactive (e.g., radionuclide). Suitable radionuclides that may beincorporated in compounds of the present invention include but are notlimited to ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N,¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵Iand ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro PD-L1 protein labelingand competition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I,¹³¹I, ³⁵S or will generally be most useful. For radio-imagingapplications C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br willgenerally be most useful. In some embodiments the radionuclide isselected from the group consisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.Synthetic methods for incorporating radio-isotopes into organiccompounds are known in the art.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a PD-L1 protein bymonitoring its concentration variation when contacting with the PD-L1protein, through tracking of the labeling. For example, a test compound(labeled) can be evaluated for its ability to reduce binding of anothercompound which is known to bind to a PD-L1 protein (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the PD-L1 protein directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

VI. Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of PD-L1 including its interaction with other proteins suchas PD-1 and B7-1 (CD80), such as cancer or infections, which include oneor more containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I′) or (I),or any of the embodiments thereof. Such kits can further include one ormore of various conventional pharmaceutical kit components, such as,e.g., containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of PD-1/PD-L1 protein/protein interaction according to atleast one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Open Access Preparative LCMS Purification of some of thecompounds prepared was performed on Waters mass directed fractionationsystems. The basic equipment setup, protocols and control software forthe operation of these systems have been described in detail inliterature. See, e.g., Blom, “Two-Pump At Column Dilution Configurationfor Preparative LC-MS”, K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blomet al., “Optimizing Preparative LC-MS Configurations and Methods forParallel Synthesis Purification”, J. Combi. Chem., 2003, 5, 670-83; andBlom et al., “Preparative LC-MS Purification: Improved Compound SpecificMethod Optimization”, J. Combi. Chem., 2004, 6, 874-883.

Example 12-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl]methyl}amino)ethanol

Step 1: (2-bromoimidazo[1,2-a]pyridin-6-yl)methanol

To a solution of methyl 2-bromoimidazo[1,2-a]pyridine-6-carboxylate (200mg, 0.784 mmol) (Ark Pharm, cat#AK-31669) in tetrahydrofuran (5.0 mL) at0° C. was added 1.0 M diisobutylaluminum hydride in tetrahydrofuran (862μL, 0.862 mmol). The resulting mixture was stirred at room temperaturefor 1 h then it was quenched with saturated NH₄Cl aqueous solution (1mL), stirred for 1 h then filtered through celite. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was used fornext step without further purification. LC-MS calculated for C₈H₈BrN₂O(M+H)⁺: m/z=227.0; found 227.2.

Step 2: 2-bromoimidazo[1,2-a]pyridine-6-carbaldehyde

To a suspension of the crude (2-bromoimidazo[1,2-a]pyridin-6-yl)methanolfrom Step 1 in methylene chloride (5.0 mL) was added Dess-Martinperiodinane (499 mg, 1.18 mmol). The resulting mixture was stirred atroom temperature for 30 min then quenched with sat'd NaHCO₃ solution.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 10% MeOH/DCM to give the desired product (156 mg,88%). LC-MS calculated for C₈H₆BrN₂O (M+H)⁺: m/z=225.0; found 225.2.

Step 3: 2-{[(2-bromoimidazo[1,2-a]pyridin-6-yl)methyl]amino}ethanol

To a solution of 2-bromoimidazo[1,2-a]pyridine-6-carbaldehyde (20 mg,0.09 mmol) and ethanolamine (7.0 mg, 0.12 mmol) in acetonitrile (1.0 mL)was added sodium triacetoxyborohydride (28 mg, 0.13 mmol). The resultingmixture was stirred at room temperature for overnight then concentrated.The residue was used for next step without further purification. LC-MScalculated for C₁₀H₁₃BrN₃O (M+H)⁺: m/z=270.0; found 270.2.

Step 4:4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane

A mixture of 3-chloro-2-methylbiphenyl (0.440 mL, 2.47 mmol) (Aldrich,cat#361623),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1.88 g,7.40 mmol), palladium acetate (22.2 mg, 0.0987 mmol), K₃PO₄ (1.57 g,7.40 mmol) and 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl(101 mg, 0.247 mmol) in 1,4-dioxane (10 mL) was purged with nitrogenthen stirred at room temperature for 48 h. The reaction mixture wasdiluted with dichloromethane (DCM), then washed over water and brine.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 5% EtOAc/DCM to give the desired product (656 mg,90%). LC-MS calculated for C₁₉H₂₄BO₂ (M+H)⁺: m/z=295.2; found 295.2.

Step 5:2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl]methyl}amino)ethanol

To a mixture of2-{[(2-bromoimidazo[1,2-a]pyridin-6-yl)methyl]amino}ethanol (9 mg, 0.03mmol), 4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane(10 mg, 0.03 mmol) and sodium carbonate (8.58 mg, 0.0809 mmol) intert-butyl alcohol (0.4 mL) and water (0.2 mL) was addeddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (3 mg,0.00324 mmol). The resulting mixture was purged with nitrogen, thenheated to 105° C. and stirred for 4 h. The reaction mixture was cooledto room temperature then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₃H₂₄N₃O (M+H)⁺: m/z=358.4; found 358.2.

Example 22-({[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}amino)ethanol

Step 1: ethyl 2-bromoindolizine-7-carboxylate

A mixture of 4-bromo-1H-pyrrole-2-carbaldehyde (Apollo, cat#AS422081:511 mg, 2.94 mmol), ethyl 4-bromocrotonate (Aldrich, cat#E13830: 1130mg, 5.87 mmol) and potassium carbonate (893 mg, 6.46 mmol) in N,N-dimethylformamide (DMF, 8 mL) was stirred overnight at roomtemperature. The reaction mixture was diluted with EtOAc then washedwith water and brine. The organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash chromatography on asilica gel column eluting with 0 to 30% EtOAc/hexanes to give thedesired product as a yellow solid. LC-MS calculated for C₁₁H₁₁BrNO₂(M+H)⁺: m/z=268.0; found 268.0.

Step 2: (2-bromoindolizin-7-yl)methanol

To a solution of ethyl 2-bromoindolizine-7-carboxylate (167 mg, 0.623mmol) in THF (1 mL) was added lithium tetrahydroaluminate in THF (1.0 M,400 μL, 0.4 mmol) dropwise at 0° C. The mixture was slowly warmed up toroom temperature and stirred for 1 h then the mixture was quenched withEtOAc, followed by water and sodium hydroxide solution. The mixture wasextracted with EtOAc three times. The organic phase was combined, driedover Na₂SO₄, filtered and concentrated. The residue was purified byflash chromatography on a silica gel column eluting with 0 to 60%EtOAc/hexanes to give the desired product. LC-MS calculated for C₉H₉BrNO(M+H)⁺: m/z=226.0; found 225.9.

Step 3: 2-bromoindolizine-7-carbaldehyde

To a solution of (2-bromoindolizin-7-yl)methanol (44.0 mg, 0.195 mmol)in methylene chloride (1.5 mL) was added Dess-Martin periodinane (82.6mg, 0.195 mmol) at room temperature. The reaction mixture was stirredfor 10 min then quenched with NaHCO₃ solution and Na₂S₂O₃ solution. Themixture was extracted with methylene chloride. The organic phase wascombined, dried over MgSO₄ and concentrated. The residue was used in thenext step without further purification. LC-MS calculated for C₉H₇BrNO(M+H)⁺: m/z=224.0; found 223.9.

Step 4: 2-{[(2-bromoindolizin-7-yl)methyl]amino}ethanol

To the crude product from Step 3 was added a solution of ethanolamine(23 μL, 0.39 mmol) in methylene chloride (2 mL). The mixture was stirredfor 20 min at room temperature then sodium triacetoxyborohydride (82 mg,0.39 mmol) and acetic acid (1 drop) were added. The mixture was stirredat room temperature for 2 h then quenched by NH₄OH solution andextracted with EtOAc three times. The organic phase was combined, driedover MgSO₄ and concentrated. The residue was used in the next stepwithout further purification. LC-MS calculated for C₁₁H₁₄BrN₂O (M+H)⁺:m/z=269.0; found 269.0.

Step 5:2-({[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}amino)ethanol

To a solution of the crude product from Step 4 in 1,4-dioxane (1 mL) andwater (0.2 mL) were added4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane(Example 1, Step 4: 57 mg, 0.20 mmol), potassium phosphate (69 mg, 0.32mmol) anddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (10 mg,0.01 mmol). The resulting mixture was purged with N₂ then stirred at 90°C. for 4 h. The reaction mixture was cooled to room temperature thendiluted with EtOAc and washed with water. The organic phase was driedover MgSO₄, filtered and concentrated. The residue was dissolved in MeOHthen purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₄H₂₅N₂O (M+H)⁺:m/z=357.2; found 357.2.

Example 3(2S)-1-{[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}piperidine-2-carboxylicacid

Step 1: methyl(2S)-1-[(2-bromoindolizin-7-yl)methyl]piperidine-2-carboxylate

To a mixture of methyl (2S)-piperidine-2-carboxylate hydrogen chloride(180 mg, 1.0 mmol) and 2-bromoindolizine-7-carbaldehyde (75 mg, 0.33mmol) in CH₂Cl₂ (2 mL) at room temperature was addedN,N-diisopropylethylamine (170 μL, 1.0 mmol), followed by acetic acid(100 μL, 2 mmol). The reaction mixture was stirred for 1 h then sodiumtriacetoxyborohydride (280 mg, 1.3 mmol) was added. After stirring atroom temperature for 4 h, the reaction mixture was quenched with NH₄OHsolution then extracted with CH₂Cl₂ three times. The organic phase wascombined, dried over MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 40% EtOAc/hexanes to give the desired product. LC-MS calculated forC₁₆H₂₀BrN₂O₂ (M+H)⁺: m/z=351.1; found 351.0.

Step 2: methyl(2S)-1-{[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}piperidine-2-carboxylate

To a solution of methyl(2S)-1-[(2-bromoindolizin-7-yl)methyl]piperidine-2-carboxylate (productfrom Step 1) in 1,4-dioxane (0.3 mL) and water (0.06 mL) was added4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane(Example 1, Step 4: 18 mg, 0.060 mmol), potassium phosphate (17 mg,0.078 mmol) anddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (2 mg,0.003 mmol). The mixture was purged with N₂, then heated at 90° C. for 4h. The reaction mixture was cooled to room temperature, diluted withEtOAc then washed with water and brine. The organic phase was dried overMgSO₄, filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 0 to 50%EtOAc/Hexanes to give the desired product. LC-MS calculated forC₂₉H₃₁N₂O₂ (M+H)⁺: m/z=439.2; found 439.2.

Step 3: (2S)-1-{[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}piperidine-2-carboxylic acid

To a mixture of methyl(2S)-1-{[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}piperidine-2-carboxylate(14 mg, 0.032 mmol) in tetrahydrofuran (THF, 0.3 mL) and MeOH (0.3 mL)was added lithium hydroxide monohydrate (20 mg, 0.4 mmol) and water (0.3mL). The resulting mixture was stirred at room temperature overnight.The reaction mixture was diluted with MeOH then purified by prep-HPLC(pH=10, acetonitrile/water+NH₄OH) to give the desired product. LC-MScalculated for C₂₈H₂₉N₂O₂ (M+H)⁺: m/z=425.2; found 425.2.

Example 4(2S)-1-{[6-(2-methylbiphenyl-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl]methyl}piperidine-2-carboxylicacid

Step 1: 6-bromopyrrolo[1,2-c]pyrimidine-3-carbaldehyde

To a solution of ethyl 6-bromopyrrolo[1,2-c]pyrimidine-3-carboxylate(D-L chiral chemicals, cat#ST-KS-041: 119 mg, 0.442 mmol) in CH₂Cl₂ (4mL) was added diisobutylaluminum hydride in CH₂Cl₂ (1.0 M, 440 μL, 0.44mmol) dropwise at −78 OC. The mixture was slowly warmed up to roomtemperature and stirred for 3 h. Then the reaction mixture was quenchedwith EtOAc followed by (NH₄)₂SO₄ solution then extracted with EtOActhree times. The organic phase was combined, dried over MgSO₄, filteredand concentrated. The residue was purified by flash chromatography on asilica gel column eluting with 0 to 50% EtOAc/Hexanes to give thedesired product. LC-MS calculated for C₈H₆BrN₂O (M+H)⁺: m/z=225.0; found224.9.

Step 2: methyl(2S)-1-[(6-bromopyrrolo[1,2-c]pyrimidin-3-yl)methyl]piperidine-2-carboxylate

To a solution of 6-bromopyrrolo[1,2-c]pyrimidine-3-carbaldehyde (9.0 mg,0.040 mmol) and methyl (2S)-piperidine-2-carboxylate[1.0]-hydrogenchloride (18 mg, 0.10 mmol) in CH₂Cl₂ (0.2 mL) were addeddiisopropylethylamine (17.4 μL, 0.10 mmol) and acetic acid (7 μL, 0.1mmol) at room temperature. The mixture was stirred for 2 h then sodiumtriacetoxyborohydride (30 mg, 0.2 mmol) was added. The reaction mixturewas stirred at room temperature for 3 h then quenched by NH₄OH solutionand extracted with CH₂Cl₂ three times. The organic phase was combined,dried over MgSO₄, filtered and concentrated. The residue was used in thenext step without further purification. LC-MS calculated forC₁₅H₁₉BrN₃O₂(M+H)⁺: m/z=352.1; found 352.0.

Step 3: Methyl(2S)-1-{[6-(2-methylbiphenyl-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl]methyl}piperidine-2-carboxylate

To the mixture of the crude product from Step 2 in 1,4-dioxane (0.3 mL)and water (0.07 mL) was added4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane(Example 1, Step 4: 21 mg, 0.070 mmol), potassium phosphate (20. mg,0.092 mmol) and dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (3 mg, 0.004 mmol). The mixture was purged withN₂, then heated at 90° C. for 4 h. The reaction mixture was cooled toroom temperature, diluted with EtOAc then washed with water and brine.The organic phase was dried over MgSO₄, filtered and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 60% EtOAc/hexanes to give the desired product. LC-MScalculated for C₂₈H₃₀N₃O₂ (M+H)⁺: m/z=440.2; found 440.2.

Step 4:(2S)-1-{[6-(2-methylbiphenyl-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl]methyl}piperidine-2-carboxylicacid

To a solution of methyl(2S)-1-{[6-(2-methylbiphenyl-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl]methyl}piperidine-2-carboxylate(6.7 mg, 0.015 mmol) in THF (0.1 mL) and MeOH (0.1 mL) was added lithiumhydroxide monohydrate (8 mg, 0.2 mmol) and water (0.1 mL). The resultingmixture was stirred at room temperature overnight then diluted with MeOHand purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₇H₂₈N₃O₂ (M+H)⁺:m/z=426.2; found 426.2.

Example 52-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamino)ethanol

Step 1: 1-(2-methylbiphenyl-3-yl)ethanone

To a solution of 1-(3-bromo-2-methylphenyl)ethanone (AstaTech,cat#CL9266: 4.2 g, 20. mmol) in water (10 mL) and 1,4-dioxane (45 mL)were added potassium phosphate (8.4 g, 39 mmol), phenylboronic acid (2.6g, 22 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.8 g, 1 mmol). The resulting mixture was purged with nitrogen thenstirred at 100° C. for 30 mins. The reaction mixture was cooled to roomtemperature then diluted with ethyl acetate, washed with water andbrine. The organic layer was dried over MgSO₄, filtered, thenconcentrated. The residue was purified by silica gel chromatographyeluting with 0-50% ethyl acetate in hexanes to afford the desiredproduct (3.95 g, 95%) as light yellowish oil. LC-MS calculated forC₁₅H₁₅O (M+H)⁺: m/z=211.3; found 211.3.

Step 2: 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone

To a solution of 1-(2-methylbiphenyl-3-yl)ethanone (1.25 g, 5.94 mmol)in ethyl acetate (30 mL) was added copper(II) bromide (5.3 g, 24 mmol).The reaction mixture was stirred at 80° C. for 2 hours then cooled toroom temperature, filtered and concentrated to dryness under reducedpressure. The residue was purified by silica gel chromatography using0-50% ethyl acetate in hexanes to afford desired product (1.51 g, 87%)as light yellowish oil. LC-MS calculated for C₁₅H₁₄BrO (M+H)⁺:m/z=289.0; found 289.0.

Step 3: 6-bromo-1,2,4-triazin-3-amine

To a solution of 1,2,4-triazin-3-amine (Aldrich, cat#100625: 5.0 g, 52mmol) in acetonitrile (50 mL) and water (70 mL) was addedN-bromosuccinimide (9.72 g, 54.6 mmol). The resulting mixture wasstirred at room temperature for 2 hours then diluted with 100 mLsaturated NaHCO₃ solution, and stirred for another 1 hour, thenextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄ then filtered and concentrated to dryness to afford thedesired product (4.5 g, 49%) as a brownish solid, which was used for thenext step without further purification.

Step 4: 6-vinyl-1,2,4-triazin-3-amine

To a solution of 6-bromo-1,2,4-triazin-3-amine (1.0 g, 5.7 mmol) inwater (3 mL) and 1,4-dioxane (17 mL) were added potassium phosphate (2.4g, 11 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich,cat#633348: 0.97 g, 6.3 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.09 g, 0.1 mmol). Theresulting mixture was purged with nitrogen then stirred at 80° C. for 30mins. The reaction mixture was cooled to room temperature, diluted withethyl acetate then washed with water and brine. Then organic layer wasdried over MgSO₄, filtered, then concentrated to dryness to afford thedesired product (580 mg, 83%) as a brownish solid which was used fornext step without further purification.

Step 5: 6-(2-methylbiphenyl-3-yl)-2-vinylimidazo[1,2-b][1,2,4]triazine

To a solution of 6-vinyl-1,2,4-triazin-3-amine (200 mg, 2 mmol) inisopropyl alcohol (6.3 mL) was added2-bromo-1-(2-methylbiphenyl-3-yl)ethanone (470 mg, 1.6 mmol). Theresulting mixture was warmed up to 90° C. and stirred for 2 hours. Thereaction mixture was cooled to room temperature then concentrated todryness. The residue was purified by silica gel chromatography using0-50% ethyl acetate in hexanes to afford desired product (200 mg, 40%)as a yellowish solid. LC-MS calculated for C₂₀H₁₇N₄(M+H)⁺: m/z=313.1;found 313.4.

Step 6:6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazine-2-carbaldehyde

To a solution of6-(2-methylbiphenyl-3-yl)-2-vinylimidazo[1,2-b][1,2,4]triazine (340 mg,1.1 mmol) in tetrahydrofuran (10 mL) and water (20 mL) was addedpotassium osmate, dihydrate (80 mg, 0.2 mmol) and sodium periodate (880mg, 4.1 mmol). The resulting mixture was stirred at room temperature for2 hours then diluted with ethyl acetate, washed with water and brine.The organic layer was dried over MgSO₄, filtered, then concentrated todryness. The residue was purified by silica gel chromatography using0-80% ethyl acetate in hexanes to afford the desired product (220 mg,64%) as a yellowish solid. LC-MS calculated for C₁₉H₁₅N₄O (M+H)⁺:m/z=315.1; found 315.2.

Step 7:2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamino)ethanol

To a solution of6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazine-2-carbaldehyde(20 mg, 0.06 mmol) in N,N-dimethylformamide (500 μL) was addedethanolamine (19 μL, 0.32 mmol) and acetic acid (18 μL, 0.32 mmol). Theresulting mixture was stirred at room temperature for 30 min then sodiumcyanoborohydride (8.0 mg, 0.13 mmol) was added. The mixture was stirredat room temperature for 2 hours then diluted with methanol and purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas the TFA salt. LC-MS calculated for C₂₁H₂₂N₅O (M+H)⁺: m/z=360.2; found360.2.

Example 62-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamino)acetonitrile

This compound was prepared using similar procedures as described forExample 5 with aminoacetonitrile replacing ethanolamine in Step 7. Theresulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₁H₁₉N₆(M+H)⁺: m/z=355.2; found 355.2.

Example 72-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamino)acetamide

This compound was prepared using similar procedures as described forExample 5 with glycinamide replacing ethanolamine in Step 7. Theresulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₁H₂₁N₆O (M+H)⁺: m/z=373.2; found 373.2.

Example 82-(methyl((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methyl)amino)ethanol

This compound was prepared using similar procedures as described forExample 5 with 2-(methylamino)ethanol replacing ethanolamine in Step 7.The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₂H₂₄N₅O (M+H)⁺: m/z=374.2; found 374.2.

Example 92-((8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylamino)ethanol

Step 1: 6-bromo-8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine

To a solution of 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone (Example 5,Step 2: 500 mg, 2 mmol) in isopropyl alcohol (7 mL) was added5-bromo-3-methylpyridin-2-amine (Aldrich, cat#525537: 320 mg, 1.7 mmol).The resulting mixture was stirred at 90° C. for 1 hour then cooled toroom temperature and concentrated to dryness. The residue was purifiedby silica gel chromatography using 0-60% ethyl acetate in hexanes toafford the desired product (299 mg, 40%) as a white solid. LC-MScalculated for C₂₁H₁₈BrN₂ (M+H)⁺: m/z=377.1; found 377.0.

Step 2: 8-methyl-2-(2-methylbiphenyl-3-yl)-6-vinylimidazo[1,2-a]pyridine

To a solution of6-bromo-8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine (229mg, 0.607 mmol) in water (0.5 mL) and 1,4-dioxane (2.5 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich, cat#633348:100 mg, 0.67 mmol), potassium phosphate (0.26 g, 1.2 mmol) and(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene]palladium(0.05 g, 0.06 mmol). The mixture was purged with nitrogen then stirredat 90° C. for 1 hour. The reaction mixture was cooled to roomtemperature then concentrated. The residue was purified by silica gelchromatography using 0-60% ethyl acetate in hexanes to afford thedesired product (197 mg, 82%) as a yellowish solid. LC-MS calculated forC₂₃H₂₁N₂ (M+H)⁺: m/z=325.2; found 325.1.

Step 3:8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine-6-carbaldehyde

To a solution of8-methyl-2-(2-methylbiphenyl-3-yl)-6-vinylimidazo[1,2-a]pyridine (162mg, 0.499 mmol) in 1,4-dioxane (3.5 mL) and water (6 mL) was addedpotassium osmate, dihydrate (20 mg, 0.05 mmol) and sodium metaperiodate(210 mg, 1.0 mmol). The resulting mixture was stirred at roomtemperature for 2 hours then diluted with water, quenched with sodiumsulfite, then extracted with ethyl acetate. The combined extract wasdried over Na₂SO₄, filtered, then concentrated to dryness under reducedpressure. The residue was purified by silica gel chromatography using0-80% ethyl acetate in hexanes to afford the desired product (57 mg,35%) as a yellowish solid. LC-MS calculated for C₂₂H₁₉N₂O (M+H)⁺:m/z=327.1; found 327.1.

Step 4:2-((8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylamino)ethanol

To a solution of8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine-6-carbaldehyde(28 mg, 0.086 mmol) in N,N-dimethylformamide (700 μL) was addedethanolamine (10. L, 0.17 mmol) and acetic acid (50 μL, 0.8 mmol). Themixture was stirred at room temperature overnight then sodiumcyanoborohydride (0.027 g, 0.43 mmol) was added. The reaction mixturewas stirred at room temperature for another 30 mins then diluted withmethanol and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) toafford desired product as TFA salt. LC-MS calculated for C₂₄H₂₆N₃O(M+H)⁺: m/z=372.2; found 372.2.

Example 10

(S)-1-((8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methyl)piperidine-2-carboxylicacid

This compound was prepared using similar procedures as described forExample 9 with (S)-piperidine-2-carboxylic acid replacing ethanolaminein Step 4. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₃₀N₃O₂ (M+H)⁺: m/z=440.2; found 440.3.

Example 112-((8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylamino)ethanol

Step 1: 5-bromo-3-chloropyridin-2-amine

To a solution of 2-amino-5-bromopyridine (Aldrich, cat#122858: 5.0 g, 29mmol) in N,N-dimethylformamide (60 mL) was added N-chlorosuccinimide(4.2 g, 32 mmol). The resulting mixture was stirred at room temperaturefor 1 hour then saturated NaHCO₃ aqueous solution was added. The mixturewas stirred for 10 min then extracted with ethyl acetate. The combinedextracts were dried over MgSO₄, filtered, and concentrated to drynessunder reduced pressure. The residue was purified by silica gelchromatography using 0-100% ethyl acetate in hexanes to afford thedesired product (4.8 g, 80%) as a yellowish solid. LC-MS calculated forC₅H₅BrClN₂ (M+H)⁺: m/z=206.9; found 206.9.

Step 2: 6-bromo-8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine

To a solution of 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone (Example 5,Step 2: 560 mg, 1.9 mmol) in isopropyl alcohol (7 mL) was added5-bromo-3-chloropyridin-2-amine (400 mg, 2 mmol). The resulting mixturewas stirred at 90° C. for 4 hours then cooled to room temperature andconcentrated to dryness under reduced pressure. The residue was purifiedby silica gel chromatography using 0-50% ethyl acetate in hexanes toafford the desired product (82 mg, 10%) as a yellowish solid. LC-MScalculated for C₂₀H₁₅BrClN₂ (M+H)⁺: m/z=397.0; found 397.0.

Step 3: 8-chloro-2-(2-methylbiphenyl-3-yl)-6-vinylimidazo[1,2-a]pyridine

To a solution of6-bromo-8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine (82 mg,0.21 mmol) in water (0.2 mL) and 1,4-dioxane (2 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich, cat#633348: 35mg, 0.23 mmol), potassium phosphate (88 mg, 0.41 mmol) and(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene]palladium(8 mg, 0.01 mmol). The resulting mixture was purged with nitrogen thenwarmed up to 70° C. and stirred for 30 mins. The reaction mixture wasthen cooled to room temperature, diluted with brine, and extracted withethyl acetate. The combined extracts were dried over MgSO₄, filtered,and then concentrated to dryness under reduced pressure. The residue waspurified with silica gel chromatography using 0-80% ethyl acetate inhexanes to afford the desired product (59 mg, 83%) as a yellowish solid.LC-MS calculated for C₂₂H₁₈ClN₂ (M+H)⁺: m/z=345.1; found 345.0.

Step 4:8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridine-6-carbaldehyde

To a solution of8-chloro-2-(2-methylbiphenyl-3-yl)-6-vinylimidazo[1,2-a]pyridine (59 mg,83%) in 1,4-dioxane (2 mL) and water (3 mL) was added sodium periodate(0.13 g, 0.62 mmol) and potassium osmate dihydrate (20 mg, 0.04 mmol).The resulting mixture was stirred at room temperature for 2 hours thendiluted with water, quenched with sodium sulfite, and extracted withethyl acetate. The combined extracts were dried over MgSO₄, filtered,and concentrated to dryness under reduced pressure. The residue was usedfor next step without further purification. LC-MS calculated forC₂₁H₁₆ClN₂O (M+H)⁺: m/z=347.1; found 347.0.

Step 5:2-((8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylamino)ethanol

To a solution of the crude product from Step 4 in N,N-dimethylformamide(2 mL) was added ethanolamine (50 μL, 0.82 mmol) and acetic acid (0.2mL, 3.5 mmol). The resulting mixture was stirred at room temperatureovernight then sodium cyanoborohydride (0.065 g, 1.0 mmol) was added.The mixture was stirred at room temperature for another 30 mins thendiluted with methanol and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to afford desired product as the TFA salt. LC-MScalculated for C₂₃H₂₃ClN₃O (M+H)⁺: m/z=392.2; found 392.1.

Example 122-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidin-6-yl]methyl}amino)ethanol

Step 1: 5-(1,3-dioxolan-2-yl)pyrimidin-2-amine

To a solution of 2-aminopyrimidine-5-carbaldehyde (Aldrich, cat#734845:200 mg, 1.62 mmol) in toluene (5 mL) were added 1,2-ethanediol (120 μL,2.1 mmol) and p-toluenesulfonic acid monohydrate (30 mg, 0.2 mmol),followed by molecular sieves (400 mg). The mixture was heated to refluxovernight. The reaction mixture was cooled to room temperature andfiltered. The filtrate was concentrated to dryness under reducedpressure and the residue was used in the next step without furtherpurification. LC-MS calculated for C₇H₁₀N₃O₂ (M+H)⁺: m/z=168.1; found168.0.

Step 2:6-(1,3-dioxolan-2-yl)-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidine

To a solution of 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone (Example 5,Step 2: 138 mg, 0.48 mmol) in isopropyl alcohol (2 mL) was added5-(1,3-dioxolan-2-yl)pyrimidin-2-amine (80. mg, 0.48 mmol) anddipotassium hydrogen phosphate (170 mg, 0.96 mmol). The reaction mixturewas stirred at 110° C. overnight. The mixture was then cooled to roomtemperature, poured into water and extracted with dichloromethane twice(20 mL). The combined organic phase was washed with brine, dried overMgSO₄, filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 0 to 25% ethylacetate/DCM to give the desired product. LC-MS calculated for C₂₂H₂₀N₃O₂(M+H)⁺: m/z=358.2; found 358.1.

Step 3: 2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidine-6-carbaldehyde

To a solution of6-(1,3-dioxolan-2-yl)-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidine(40 mg, 0.1 mmol) in tetrahydrofuran (2 mL) was added 1.0 M hydrogenchloride in water (450 μL, 0.45 mmol). The reaction solution was stirredat 50° C. for 2 hour then cooled to room temperature, diluted with DCM,washed with NaHCO₃ aqueous solution and brine. The organic layer wasdried over MgSO₄, filtered and concentrated. The residue was used in thenext step without further purification. LC-MS calculated for C₂₀H₁₆N₃O(M+H)⁺: m/z=314.1; found 314.1.

Step 4:2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidin-6-yl]methyl}amino)ethanol

To a solution of2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidine-6-carbaldehyde (15.0mg, 0.0479 mmol) in 1,2-dichloroethane (1 mL) was added ethanolamine(5.8 μL, 0.096 mmol). The mixture was stirred at room temperature for 30min, then sodium triacetoxyborohydride (30 mg, 0.14 mmol) was added. Theresulting mixture was stirred at room temperature overnight thenconcentrated. The residue was diluted with MeOH and purified byprep-HPLC (pH=10, acetonitrile/water+NH₄OH) to give the desired product.LC-MS calculated for C₂₂H₂₃N₄O (M+H)⁺: m/z=359.2; found 359.1.

Example 132-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazin-6-yl]methyl}amino)ethanol

Step 1: 2-(2-methylbiphenyl-3-yl) imidazo[1,2-a]pyrazine-6-carbonitrile

To a solution of 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone (Example 5,Step 2: 782 mg, 2.71 mmol) in isopropyl alcohol (10 mL) was added5-aminopyrazine-2-carbonitrile (Ark Pharm, cat#AK-21935: 325. mg, 2.71mmol). The resulting mixture was heated at 110° C. overnight then cooledto room temperature and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 0 to 25% ethylacetate/DCM to give the desired product. LC-MS calculated forC₂₀H₁₅N₄(M+H)⁺: m/z=311.1; found 311.1.

Step 2: [2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazin-6-yl]methanol

To a solution of2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazine-6-carbonitrile (110 mg,0.35 mmol) in methylene chloride (3 mL) was added 1.0 Mdiisobutylaluminum hydride in DCM (0.71 mL, 0.71 mmol) dropwise at −78OC. The mixture was stirred at −78 OC for 2 hours then quenched with afew drops of saturated NH₄Cl aqueous solution and diluted with saturatedsodium potassium tartrate solution. The suspension was stirred at roomtemperature overnight then extracted with DCM. The combined organiclayers were dried over MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 25% ethyl acetate/DCM to give the desired product. LC-MS calculatedfor C₂₀H₁₈N₃O (M+H)⁺: m/z=316.1; found 316.1.

Step 3: 2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazine-6-carbaldehyde

Dimethyl sulfoxide (27 μL, 0.38 mmol) was added to a solution of 2.0 Moxalyl chloride in DCM (0.095 mL, 0.19 mmol) in methylene chloride (1mL) at −78 OC. To the above solution,[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazin-6-yl]methanol (30. mg,0.095 mmol) in methylene chloride (1 mL) was slowly added and thencontinued to stir at −78° C. for 30 mins. Then N,N-diisopropylethylamine(0.13 mL, 0.76 mmol) was added. The reaction mixture was slowly warmedto 0° C. then poured into NaHCO₃ aqueous solution and extracted withDCM. The combined extracts were washed with water and brine. The organiclayer was dried over MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 25% ethyl acetate/DCM to give the desired product. LC-MS calculatedfor C₂₀H₁₆N₃O (M+H)⁺: m/z=314.1; found 314.1.

Step 4:2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazin-6-yl]methyl}amino)ethanol

To a solution of2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazine-6-carbaldehyde (15.0 mg,0.0479 mmol) in 1,2-dichloroethane (1 mL) was addedN,N-diisopropylethylamine (17 μL, 0.096 mmol) and ethanolamine (5.8 μL,0.096 mmol). The mixture was stirred at room temperature for 20 min,then sodium triacetoxyborohydride (30. mg, 0.14 mmol) was added. Thereaction mixture was stirred at room temperature for 3 h thenconcentrated. The residue was dissolved in MeOH then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₂H₂₃N₄O (M+H)⁺: m/z=359.2; found359.1.

Example 14(S)-1-((2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl)methyl)piperidine-2-carboxylicacid

Step 1: methyl2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate

Methyl 6-aminopyridazine-3-carboxylate (Accela ChemBio, cat#SY006049: 87mg, 0.57 mmol) was added to the solution of2-bromo-1-(2-methylbiphenyl-3-yl)ethanone (Example 5, Step 2: 181 mg,0.626 mmol) in isopropyl alcohol (2.3 mL). The mixture was stirred at90° C. for 2 h then cooled to room temperature and concentrated. Theresidue was purified by chromatography (15-30% EtOAc/hexanes) on silicagel to give the desired product 85 mg (43% yield). LC-MS calculated forC₂₁H₁₈N₃O₂ (M+H)⁺: m/z=344.1; found: 344.1.

Step 2: [2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl]methanol

1.0 M Diisobutylaluminum hydride in DCM (0.33 mL, 0.33 mmol) was addedto a solution of methyl2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazine-6-carboxylate (104 mg,0.303 mmol) in methylene chloride (1.5 mL) at −40 OC. The mixture waswarmed to −5° C. and stirred for 40 min and then stirred at roomtemperature overnight. The mixture was quenched with aqueous NH₄Cl andpotassium sodium tartrate, and extracted with DCM. The combined extractswere dried over Na₂SO₄, filtered and concentrated. The residue waspurified by chromatography (90-100% EtOAc) on silica gel to give thedesire product (35 mg). LC-MS calculated for C₂₀H₁₈N₃O (M+H)⁺:m/z=316.1; found: 316.1.

Step 3: 2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazine-6-carbaldehyde

Dess-Martin periodinane (66.6 mg, 0.157 mmol) was added to the solutionof [2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl]methanol (33.0mg, 0.105 mmol) in DCM (3 mL). The mixture was stirred at roomtemperature for 15 min then quenched with aqueous sodium bisulfite andextracted with Et₂O. The organic phase was dried over Na₂SO₄, filteredand concentrated. The residue was purified by chromatography (20-30%EtOAc/Hex) on silica gel to give the desired product (24 mg). LC-MScalculated for C₂₀H₁₆N₃O (M+H)⁺: m/z=314.1; found: 314.1.

Step 4:(2S)-1-{[2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl]methyl}piperidine-2-carboxylicacid

(2S)-piperidine-2-carboxylic acid (26.8 mg, 0.207 mmol) was added to asolution of2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazine-6-carbaldehyde (13.0mg, 0.0415 mmol) in N,N-dimethylformamide (0.41 mL), followed by aceticacid (3.54 μL, 0.0622 mmol). The reaction mixture was stirred at roomtemperature for 10 min. Then sodium cyanoborohydride (7.9 mg, 0.12 mmol)was added. The reaction mixture was stirred at room temperatureovernight then diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to afford the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₇N₄O₂ (M+H)⁺: m/z=427.2; found: 427.2.

Example 152-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl]methyl}amino)ethanol

This compound was prepared using similar procedures as described forExample 14 with ethanolamine replacing (2S)-piperidine-2-carboxylic acidin Step 4. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₂H₂₃N₄O (M+H)⁺: m/z=359.2; found 359.2.

Example 16 2-({[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl}amino)ethanol

Step 1: (2-amino[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanol

Ethoxycarbonyl isothiocyanate (606 μL, 5.36 mmol) was added to asolution of (2-aminopyridin-4-yl)methanol (Aldrich, cat#714577: 555 mg,4.47 mmol) in 1,4-dioxane (22.4 mL). The reaction mixture was stirred atroom temperature for 15 h. The mixture was concentrated and the residuewas dissolved in methanol (16.0 mL)/ethanol (16.0 mL), thenN,N-diisopropylethylamine (1.56 mL, 8.94 mmol) was added, followed byhydroxylamine hydrochoride (932 mg, 13.4 mmol). The reaction mixture wasstirred at 45° C. for 2 h then cooled to room temperature andconcentrated. The residue was used in the next step without furtherpurification. LC-MS calculated for C₇H₉N₄O (M+H)⁺: m/z=165.1; found:165.1.

Step 2: (2-bromo[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanol

tert-Butyl nitrite (1.28 mL, 10.7 mmol) was added to a suspension of(2-amino[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanol (734 mg, 4.47 mmol)and copper(II) bromide (2.00 g, 8.94 mmol) in acetonitrile (55 mL). Thereaction mixture was stirred at room temperature for 2 h then dilutedwith DCM and washed with water. The organic phase was dried over Na₂SO₄,filtered and concentrated. The residue was purified by chromatography onsilica gel to give the desired product as a yellow solid (842 mg, 83%yield). LC-MS calculated for C₇H₇BrN₃O (M+H)⁺: m/z=228.0; found: LC/MS:228.0.

Step 3:[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]methanol

A mixture of (2-bromo[1,2,4]triazolo[1,5-a]pyridin-7-yl)methanol (128mg, 0.564 mmol),4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane(Example 1, Step 4: 199 mg, 0.676 mmol),(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene]palladium(44.4 mg, 0.0564 mmol) and K₃PO₄ (215 mg, 1.01 mmol) in 1,4-dioxane (2.6mL)/water (0.3 mL) was purged with nitrogen then stirred at 90° C. for18 h. The mixture was cooled to room temperature then diluted with DCM,dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby chromatography (40-100% EtOAc/hexanes) on silica gel to give thedesired product as an off-white solid (85.0 mg). LC-MS calculated forC₂₀H₁₈N₃O (M+H)⁺: m/z=316.1; found: 316.1.

Step 4:2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-7-carbaldehyde

Dess-Martin periodinane (80.7 mg, 0.190 mmol) was added to the solutionof [2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]methanol(40.0 mg, 0.127 mmol) in dichloromethane (3 mL). The mixture was stirredat room temperature for 1.5 h and more Dess-Martin periodinane (1.5equiv) was added. The mixture was stirred for another 3.5 h thenquenched with aqueous sodium bisulfite and extracted withdichloromethane. The combined extracts were dried over Na₂SO₄, filteredand concentrated. The residue was purified with chromatography on silicagel to give the desired product (29 mg). LC-MS calculated for C₂₀H₁₆N₃O(M+H)⁺: m/z=314.1; found: 314.1.

Step 5:2-({[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl}amino)ethanol

Ethanolamine (7.3 mg, 0.12 mmol) was added to a solution of2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-7-carbaldehyde(7.5 mg, 0.024 mmol) in N,N-dimethylformamide (0.24 mL), followed byacetic acid (2.0 μL, 0.036 mmol). The reaction mixture was stirred atroom temperature for 10 min then sodium cyanoborohydride (4.5 mg, 0.072mmol) was added. The mixture was stirred at room temperature overnightthen diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to afford the desired product as the TFA salt.LC-MS calculated for C₂₂H₂₃N₄O (M+H)⁺: m/z=359.2; found: 359.2.

Example 17 (2S)-1-{[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl}piperidine-2-carboxylic acid

This compound was prepared using similar procedures as described forExample 16 with (2S)-piperidine-2-carboxylic acid replacing ethanolaminein Step 5. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₇N₄O₂ (M+H)⁺: m/z=427.2; found 427.2.

Example 18 2-({[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol

Step 1: methyl 2-amino[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate

To a solution of methyl 6-aminonicotinate (Aldrich, cat#648736: 699 mg,4.59 mmol) in 1,4-dioxane (23.0 mL) was added ethoxycarbonylisothiocyanate (623 μL, 5.51 mmol). The reaction mixture was stirred atroom temperature for 15 h. The crude was concentrated and the residuewas dissolved in methanol (17 mL)/ethanol (17 mL) thenN,N-diisopropylethylamine (1.6 mL, 9.2 mmol) was added, followed byhydroxyaminehydrochoride (958 mg, 13.8 mmol). The resulting mixture wasstirred at 45° C. for 2 h then cooled to room temperature andconcentrated. The residue was directly used for the next step withoutfurther purification. LC-MS calculated for C₈H₉N₄O₂(M+H)⁺: m/z=193.1;found: 193.0.

Step 2: methyl 2-bromo[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate

tert-Butyl nitrite (1.31 mL, 11.0 mmol) was added to a suspension ofmethyl 2-amino[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (883 mg, 4.59mmol) and copper(II) bromide (2.05 g, 9.19 mmol) in acetonitrile (44mL). The mixture was stirred at room temperature for 2 h then dilutedwith dichloromethane and washed with water. The organic phase was driedover Na₂SO₄, filtered and concentrated. The residue was purified bychromatography on silica gel to give the desired product as a whitesolid (483 mg, 41% yield). LC-MS calculated for C₈H₇BrN₃O₂(M+H)⁺:m/z=256.0; found: 256.0.

Step 3: methyl2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate

A mixture of methyl 2-bromo[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate(188 mg, 0.734 mmol),4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane(Example 1, Step 4: 259 mg, 0.881 mmol),(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene]palladium(57.8 mg, 0.0734 mmol) and K₃PO₄ (280 mg, 1.32 mmol) in 1,4-dioxane (3.4mL)/water (0.3 mL) was purged with nitrogen then stirred at 90° C. for15 h. The reaction mixture was cooled to room temperature andconcentrated. The residue was purified by chromatography (20-25%EtOAc/Hex) on silica gel to give the desired product as an off-whitesolid (188 mg, 75% yield). LC-MS calculated for C₂₁H₁₈N₃O₂ (M+H)⁺:344.1; found: 344.1.

Step 4:[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methanol

Diisobutylaluminum hydride in DCM (643 μL, 0.643 mmol) was added to thesolution of methyl2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate(184 mg, 0.536 mmol) in Et₂O (5 mL) at 0° C. The mixture was stirred atroom temperature for 3 h then another portion of diisobutylaluminumhydride (1M in DCM, 1 mL, 1 mmol) was added. The mixture was stirred atroom temperature for another 2 h then quenched with aqueous NH₄Cl andstirred with Rochelle salt, and then extracted with DCM. The combinedextracts were dried over Na₂SO₄, filtered and concentrated. The residuewas purified by chromatography (50-100% EtOAc) on silica gel to give thedesired product (86 mg, 51% yield). LC-MS calculated for C₂₀H₁₈N₃O(M+H)⁺: 316.1; found: 316.1.

Step 5:2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde

Dess-Martin periodinane (171 mg, 0.404 mmol) was added to a solution of[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methanol(85 mg, 0.27 mmol) in dichloromethane (3 mL). The mixture was stirred atroom temperature for 1 h then quenched with aqueous sodium bisulfite,and extracted with dichloromethane. The combined extracts were driedover Na₂SO₄, filtered and concentrated. The residue was purified withchromatography (20-40% EtOAc/Hex) on silica gel to give the desiredproduct (70 mg). LC-MS calculated for C₂₀H₁₆N₃O (M+H)⁺: m/z=314.1;found: 314.1.

Step 6:2-({[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol

Ethanolamine (8.7 μL, 0.15 mmol) was added to a solution of2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde(9.0 mg, 0.029 mmol) in N,N-dimethylformamide (0.28 mL), followed byacetic acid (2.5 μL, 0.04 mmol). The reaction mixture was stirred atroom temperature for 10 min then sodium cyanoborohydride (5.4 mg, 0.087mmol) was added. The mixture was stirred at room temperature overnightthen diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to afford the desired product as the TFA salt.LC-MS calculated for C₂₂H₂₃N₄O (M+H)⁺: m/z=359.2; found: 359.2.

Example 19 (2S)-1-{[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}piperidine-2-carboxylic acid

The title compound was prepared using similar procedures as describedfor Example 18 with (2S)-piperidine-2-carboxylic acid replacingethanolamine in Step 6. The resulting mixture was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₆H₂₇N₄O₂ (M+H)⁺: m/z=427.2; found 427.2.

Example 20 2-({[5-methyl-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]methyl}amino)ethanol

Step 1: 7-chloro-5-methyl[1,2,4]triazolo[1,5-c]pyrimidin-2-amine

To a solution of 6-chloro-2-methylpyrimidin-4-amine (AK Scientific,cat#W3822: 585 mg, 4.07 mmol) in 1,4-dioxane (20.4 mL) was addedethoxycarbonyl isothiocyanate (553 μL, 4.89 mmol). The reaction mixturewas heated at 50° C. for 6 h then cooled to room temperature andconcentrated. The residue was dissolved in methanol (15 mL)/ethanol (15mL) then N,N-diisopropylethylamine (1.42 mL, 8.15 mmol) was added,followed by hydroxylamine hydrochoride (849 mg, 12.2 mmol). The mixturewas stirred at 50° C. for 3 h then cooled to room temperature andconcentrated. The residue was directly used for the next step withoutfurther purification. LC-MS calculated for C₆H₇ClN₅ (M+H)⁺: m/z=184.0;found 184.0.

Step 2: 7-chloro-2-iodo-5-methyl[1,2,4]triazolo[1,5-c]pyrimidine

tert-Butyl nitrite (1.16 mL, 9.78 mmol) was added to a suspension of7-chloro-5-methyl[1,2,4]triazolo[1,5-c]pyrimidin-2-amine (crude productfrom Step 1) and copper(I) iodide (1.55 g, 8.15 mmol) in acetonitrile(39.4 mL). The mixture was heated at 70° C. for 2 h then cooled to roomtemperature, diluted with dichloromethane and washed with water. Theorganic phase was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel to give the desiredproduct as a yellow solid (61.0 mg). LC-MS calculated for C₆H₅ClN₄(M+H)⁺: m/z=294.9; found 294.9.

Step 3:5-methyl-2-(2-methylbiphenyl-3-yl)-7-vinyl[1,2,4]triazolo[1,5-c]pyrimidine

A mixture of 7-chloro-2-iodo-5-methyl[1,2,4]triazolo[1,5-c]pyrimidine(61 mg, 0.21 mmol),4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane(Example 1, Step 4: 67 mg, 0.23 mmol),(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene]palladium(16 mg, 0.02 mmol) and K₃PO₄ (79 mg, 0.37 mmol) in 1,4-dioxane (0.96mL)/water (75 μL) was purged with nitrogen then heated at 90° C. for 3h. The reaction mixture was cooled to room temperature then4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (105 μL, 0.62 mmol) wasadded, followed by (2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphoranylidene]palladium(16 mg, 0.02 mmol) and K₃PO₄ (79 mg, 0.37 mmol). The mixture was purgedwith nitrogen again and stirred at 90° C. for 3 h. The reaction mixturewas cooled to room temperature, diluted with dichloromethane then driedover Na₂SO₄, filtered and concentrated. The residue was purified bychromatography (8-15% EtOAc/Hex) on silica gel to give the desiredproduct as an off-white solid. LC-MS calculated for C₂₁H₁₉N₄ (M+H)⁺:m/z=327.2; found 327.1.

Step 4: 5-methyl-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-c]pyrimidine-7-carbaldehyde

Potassium osmate dihydrate (0.96 mg, 0.0026 mmol) and sodium periodate(5.85 mg, 0.0273 mmol) were added to the solution of5-methyl-2-(2-methylbiphenyl-3-yl)-7-vinyl[1,2,4]triazolo[1,5-c]pyrimidine(8.5 mg, 0.026 mmol) in tetrahydrofuran (0.07 mL) and water (0.11 mL).The mixture was stirred at room temperature for 1 h then diluted withethyl acetate and washed with water. The organic phase was dried overNa₂SO₄, filtered and concentrated. The residue was directly used for thenext step without further purification. LC-MS calculated for C₂₀H₁₇N₄O(M+H)⁺: m/z=329.1; found 329.2.

Step 5:2-({[5-methyl-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]methyl}amino)ethanol

Ethanolamine (5.9 μL, 0.097 mmol) was added to the solution of5-methyl-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-c]pyrimidine-7-carbaldehyde(6.4 mg, 0.019 mmol) in N,N-dimethylformamide (0.19 mL), followed byacetic acid (1.7 μL, 0.029 mmol). The mixture was stirred at roomtemperature for 10 min then sodium cyanoborohydride (3.7 mg, 0.059 mmol)was added. The mixture was stirred at room temperature overnight thendiluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to afford the desired product as the TFA salt.LC-MS calculated for C₂₂H₂₄N₅O (M+H)⁺: m/z=374.2; found: 374.2.

Example 212-({[8-chloro-2-(2-methylbiphenyl-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol

Step 1: ethyl({[3-chloro-5-(hydroxymethyl)pyridin-2-yl]amino}carbonothioyl)carbamate

To a solution of (6-amino-5-chloropyridin-3-yl)methanol (551 mg, 3.47mmol) in 1,4-dioxane (8.8 mL) was added ethoxycarbonyl isothiocyanate(471 μL, 4.17 mmol). The reaction mixture was stirred at roomtemperature for 15 h. The precipitate was filtered and washed withdichloromethane. The mother liquor was concentrated and filtered again.Two crops of the solid were collected and dried to give the desiredproduct 599 mg (60% yield). LC-MS calculated for C₁₀H₁₃ClN₃O₃S (M+H)⁺:m/z=290.0; found: 290.0.

Step 2: (2-amino-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol

Hydroxyaminehydrochloride (423 mg, 6.09 mmol) was added to a solution ofethyl({[3-chloro-5-(hydroxymethyl)pyridin-2-yl]amino}carbonothioyl)carbamate(588 mg, 2.03 mmol) in methanol (7.5 mL)/ethanol (7.5 mL), followed byN,N-diisopropylethylamine (0.707 mL, 4.06 mmol). The reaction mixturewas then heated at 50° C. for 1.5 h. The crude was concentrated. Theresidue was directly used in the next step. LC-MS calculated forC₇H₈ClN₄O (M+H)⁺: m/z=199.0; found: 199.0.

Step 3: (2-bromo-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol

tert-Butyl nitrite (579 μL, 4.87 mmol) was added to a suspension of(2-amino-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol (403 mg,2.03 mmol) and copper(II) bromide (906 mg, 4.06 mmol) in acetonitrile(19.6 mL). The mixture was stirred at room temperature for 3 h. Thereaction mixture was diluted with dichloromethane and washed with water.The organic phase was dried, filtered and concentrated. The residue waspurified by chromatography on silica gel (50-75% EtOAc/Hex) to give thedesired product as a white solid (428 mg, 82% yield, two steps). LC-MScalculated for C₇H₆BrClN₃O (M+H)⁺: m/z=261.9; found: 261.9.

Step 4: [8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methanol

A mixture of(2-bromo-8-chloro[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol (350 mg,1.33 mmol),4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane(Example 1, Step 4: 392 mg, 1.33 mmol), K₃PO₄ (509 mg, 2.40 mmol) andtetrakis(triphenylphosphine)palladium(0) (385 mg, 0.333 mmol) in1,4-dioxane (6.18 mL)/water (480 μL) was stirred and heated at 110° C.for 4 h. The crude mixture was dried over a drying agent and filtered.The filtrate was concentrated. The residue was purified bychromatography (40-60% EtOAc/Hex) on silica gel to give the desiredproduct 291 mg (63% yield). LC-MS calculated for C₂₀H₁₇ClN₃O (M+H)⁺:m/z=350.1; found: 350.1.

Step 5: 8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde

Dess-Martin periodinane (706 mg, 1.66 mmol) was added to a solution of[8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methanol (291 mg, 0.832 mmol) indichloromethane (3.94 mL). The mixture was stirred at room temperaturefor 1 h. The mixture was quenched with aq. sodium bisulfite andextracted with dichloromethane. The organic phase was dried over adrying agent and filtered. The filtrate was concentrated. The residuewas purified by chromatography (15-25% EtOAc/Hex) on silica gel to givethe desired product (215 mg, 74% yield) as a white solid. LC-MScalculated for C₂₀H₁₅ClN₃O (M+H)⁺: m/z=348.1; found: 348.1.

Step 6:2-({[8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol

Ethanolamine (186 μL, 3.09 mmol) was added to a solution of8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridine-6-carbaldehyde(215 mg, 0.618 mmol) in N,N-dimethylformamide (3.87 mL), followed bytrifluoroacetic acid (143 μL). The reaction mixture was stirred at roomtemperature for 10 min. Then sodium cyanoborohydride (116 mg, 1.85 mmol)was added. The reaction mixture was stirred at room temperatureovernight. The crude was diluted with water and extracted withdichloromethane. The organic phase was concentrated. The residue waspurified by chromatography on silica gel (5-15% MeOH/DCM) to give thedesired product 188 mg (77% yield). LC-MS calculated for C₂₂H₂₂ClN₄O(M+H)⁺: m/z=393.1; found: 393.1.

Example 22 2-({[8-[(2-methoxyethyl)amino]-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol

[(2-Di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate methanesulfonate (Brettphos-Pd-G3, Aldrich, cat#761605:3.7 mg, 0.0041 mmol) was added to a mixture of2-({[8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol (8.0 mg, 0.020 mmol), cesium carbonate (13.3 mg, 0.0407mmol) and 2-methoxyethylamine (5.3 μL, 0.061 mmol) in 1,4-dioxane (152μL). The mixture was stirred at 100° C. for 45 min. The crude wasdiluted with MeOH and filtered. The filtrate was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to afford the desired product as the TFAsalt. LC-MS calculated for C₂₅H₃₀N₅O₂ (M+H)⁺: m/z=432.2; found: 432.2.

Example 234-[6-{[(2-hydroxyethyl)amino]methyl}-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-8-yl]butanenitrile

Chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(RuPhos-Pd-G2, Aldrich, cat#753246: 1.6 mg, 0.0020 mmol) was added to amixture of2-({[8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol (Example 21: 8.0 mg, 0.02 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butanenitrile (7.9 mg,0.041 mmol) and cesium carbonate (13.3 mg, 0.0407 mmol) in 1,4-dioxane(94.5 μL)/water (31.1 μL). The mixture was stirred at 100° C. for 1 h.The crude was diluted with MeOH and filtered. The filtrate was purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to afford the desiredproduct as the TFA salt. LC-MS calculated for C₂₆H₂₈N₅O (M+H)⁺:m/z=426.2; found: 426.3.

Example 24 [6-{[(2-hydroxyethyl)amino]methyl}-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-8-yl]acetonitrile

Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos-Pd-G2, Aldrich,cat#741825: 4.8 mg, 0.0061 mmol) was added to a mixture of2-({[8-chloro-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol (Example 21: 12.0 mg, 0.0305 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (8.94 mg,0.0458 mmol) and potassium phosphate (19.4 mg, 0.0916 mmol) in1,4-dioxane (188 μL, 2.41 mmol)/water (11.0 μL, 0.611 mmol). The mixturewas stirred at 100° C. for 2 h. The crude was diluted with MeOH andfiltered through Celite. The filtrate was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to afford the desired product as the TFA salt.LC-MS calculated for C₂₄H₂₄N₅O (M+H)⁺: m/z=398.2; found: 398.2.

Example 252-(8-chloro-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile

Step 1: 2-bromo-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile

A mixture of 2-bromo-6-iodobenzonitrile (3.01 g, 9.78 mmol),2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (1.60 g, 8.89 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (363 mg, 0.444 mmol) and potassium carbonate(3.07 g, 22.2 mmol) in 1,4-dioxane (36.0 mL, 462 mmol) and water (1.60mL, 88.9 mmol) was degassed and recharged with nitrogen. The mixture wasthen heated and stirred at 75° C. for 4 h. The reaction mixture wasdried over a drying agent and filtered. The filtrate was concentrated.The residue was purified by chromatography on silica gel (10-15%EtOAc/Hex) to afford the desired product 1.48 g. LC-MS calculated forC₁₅H₁₁BrNO₂ (M+H)⁺: m/z=316.0 and 318.0; found: 316.0 and 318.0.

Step 2:2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A mixture of 2-bromo-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile(1.20 g, 3.80 mmol), Bis(pinacolato)diboron (1.06 g, 4.18 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (150 mg, 0.19 mmol), potassium acetate (1.1g, 11 mmol) in 1,4-dioxane (30 mL, 400 mmol) was degassed for 5 min, andthen stirred at 90° C. for 4 h. The crude was diluted withdichloromethane and then filtered. The filtrate was concentrated. Theresidue was purified by chromatography on silica gel to afford thedesired product. LC-MS calculated for C₂₁H₂₃BNO₄ (M+H)⁺: m/z=364.2;found: 364.2.

Step 3:2-(8-chloro-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 21. The resulting crude was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₄H₂₁ClN₅O₃(M+H)⁺: m/z=462.1; found: 462.1.

Example 262-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile

A mixture of2-(8-chloro-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile(Example 25: 6.0 mg, 0.013 mmol), potassium hexacyanoferrate(II)trihydrate (5.49 mg, 0.0130 mmol), and potassium acetate (0.255 mg,0.00260 mmol) in 1,4-dioxane (32.2 μL)/water (32.2 μL) was stirred andheated at 100° C. for 1 h. The resulting crude was diluted with MeOH andfiltered. The filtrate was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₅H₂₁N₆O₃ (M+H)⁺: m/z=453.2; found: 453.2.

Example 272-(8-(cyanomethyl)-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 24. The resulting crude was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₃N₆O₃ (M+H)⁺: m/z=467.2; found: 467.2.

Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF)Binding Assay

The assays were conducted in a standard black 384-well polystyrene platewith a final volume of 20 μL. Inhibitors were first serially diluted inDMSO and then added to the plate wells before the addition of otherreaction components. The final concentration of DMSO in the assay was1%. The assays were carried out at 25° C. in the PBS buffer (pH 7.4)with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein(19-238) with a His-tag at the C-terminus was purchased fromAcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) withFc tag at the C-terminus was also purchased from AcroBiosystems(PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay bufferand 10 μL was added to the plate well. Plates were centrifuged andproteins were preincubated with inhibitors for 40 minutes. Theincubation was followed by the addition of 10 μL of HTRF detectionbuffer supplemented with Europium cryptate-labeled anti-human IgG(PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated toSureLight®-Allophycocyanin (APC, PerkinElmer-AD0059H). Aftercentrifugation, the plate was incubated at 25° C. for 60 min. beforereading on a PHERAstar FS plate reader (665 nm/620 nm ratio). Finalconcentrations in the assay were—3 nM PD1, 10 nM PD-L1, 1 nM europiumanti-human IgG and 20 nM anti-His-Allophycocyanin. IC₅₀ determinationwas performed by fitting the curve of percent control activity versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

Compounds of the present disclosure, as exemplified in Examples 1-20,showed IC₅₀ values in the following ranges: +=IC₅₀≤100 nM; ++=100nM<IC₅₀≤500 nM; +++=500 nM<IC₅₀≤10000 nM

Data obtained for the Example compounds using the PD-1/PD-L1 homogenoustime-resolved fluorescence (HTRF) binding assay described in Example Ais provided in Table 1.

TABLE 1 PD-1/PD-L1 HTRF Example IC₅₀ (nM) 1 ++ 2 ++ 3 ++ 4 +++ 5 + 6 ++7 ++ 8 ++ 9 ++ 10 ++ 11 ++ 12 ++ 13 + 14 +++ 15 ++ 16 + 17 ++ 18 + 19 ++20 + 21 + 22 ++ 23 + 24 + 25 + 26 + 27 +

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

What is claimed is:
 1. A compound of Formula (I′):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: one of Y¹ and Y² is N and the other of Y¹ and Y² is C; X¹ is Nor CR^(i); X² is N or CR²; X³ is N or CR³; X⁴ is N or CR⁴; X⁵ is N orCR⁵; X⁶ is N or CR⁶; Cy is C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5- to14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, each ofwhich is optionally substituted with 1 to 4 independently selected R⁷substituents; Z¹ is N or CR^(8a); Z² is N or CR^(8b); Z³ is N orCR^(8c); R¹, R², R^(8a), R^(8b) and R^(8c) are each independentlyselected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄alkyl-, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₂₋₄ alkenyl, C₂₋₄alkynyl, halo, CN, OR¹⁰, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NHR¹⁰,—NR¹⁰R¹⁰, NHOR¹⁰, C(O)R¹⁰, C(O)NR¹⁰R¹⁰, C(O)OR¹⁰, OC(O)R¹⁰,OC(O)NR¹⁰R¹⁰, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)OR¹⁰, NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰,C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰,NR¹⁰S(O)₂NR¹⁰R¹⁰, S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and S(O)₂NR¹⁰R¹⁰,wherein each R¹⁰ is independently selected from H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄ alkyl-, C₆₋₁₀ aryl, C₆₋₁₀ aryl-C₁₋₄ alkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-, C₆₋₁₀ aryl, C₆₋₁₀aryl-C₁₋₄ alkyl-, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹, R², R^(8a), R^(8b), R^(8c)and R¹⁰ are each optionally substituted with 1, 2 or 3 independentlyselected R^(b) substituents; R⁹ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR¹¹, —SR¹¹, —NH₂, NHR¹¹, NR¹¹R¹¹, NHOR¹¹, C(O)R¹¹,C(O)NR¹¹R¹¹, C(O)OR¹¹, OC(O)R¹¹, OC(O)NR¹¹R¹¹, NR¹¹C(O)R¹¹,NR^(i)C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹¹, C(═NR¹¹)R¹¹, C(═NR¹¹)NR¹¹R¹¹,NR¹¹C(═NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹, NR¹¹S(O)₂NR¹¹R¹¹,S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and S(O)₂NR¹¹R¹¹, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁹ are each optionally substituted with1, 2 or 3 R^(b) substituents; each R¹¹ is independently selected from H,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹¹ are each optionallysubstituted with 1, 2 or 3 independently selected R^(b) substituents;R³, R⁴, R⁵, R⁶ and R⁷ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵, R⁶ and R⁷ are eachoptionally substituted with 1, 2, 3, or 4 R^(b) substituents, with theproviso that at least one of R³, R⁴, R⁵ and R⁶ is other than H; or twoadjacent R⁷ substituents on the Cy ring, taken together with the atomsto which they are attached, form a fused phenyl ring, a fused 5-, 6- or7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroarylring or a fused C₃₋₆ cycloalkyl ring, wherein the fused 5-, 6- or7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroarylring each have 1-4 heteroatoms as ring members selected from N, O and Sand wherein the fused phenyl ring, fused 5-, 6- or 7-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(b) substituents; each R^(a) is independentlyselected from H, CN, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents; each R^(d) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NH₂, NHOR^(e), OR^(e), SR^(e),C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e),NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e),NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NOH)NR^(e)R^(e), NR^(e)C(═NCN)NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(d) are each optionally substitutedwith 1-3 independently selected R^(h) substituents; each R^(b)substituent is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each furtheroptionally substituted with 1-3 independently selected R^(d)substituents; each R^(c) is independently selected from H, C₁₋₆ alkyl,C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(c) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(f) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g), OR^(g), SR^(g),C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g), OC(O)NR^(g)R^(g),NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g), NR^(g)C(O)NR^(g)R^(g),NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g), NR^(g)C(═NR^(g))NR^(g)R^(g),S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g), NR^(g)S(O)₂R^(g),NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); wherein the C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl- of R^(f) are each optionally substituted with 1, 2, 3, 4, or 5R^(n) substituents independently selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, halo, CN, NHOR^(o), OR^(o), SR^(o), C(O)R^(o),C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o), NHR^(o),NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o), NR^(o)C(O)OR^(o),C(═NR)NR^(o)R^(o), NR^(o)C(═NR)NR^(o)R^(o), S(O)R^(o), S(O)NR^(o)R^(o),S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o), andS(O)₂NR^(o)R^(o); each R^(g) is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionally substitutedwith 1-3 R^(p) substituents independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-(5-10 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,halo, CN, NHOR^(r), OR^(r), SR^(r), C(O)R^(r), C(O)NR^(r)R^(r),C(O)OR^(r), OC(O)R^(r), OC(O)NR^(r)R^(r), NHR^(r), NR^(r)R^(r),NR^(r)C(O)R^(r), NR^(r)C(O)NR^(r)R^(r), NR^(r)C(O)OR^(r),C(═NR^(r))NR^(r)R^(r), NR^(r)C(═NR^(r))NR^(r)R^(r),NR^(r)C(═NOH)NR^(r)R^(r), NR^(r)C(═NCN)NR^(r)R^(r), S(O)R^(r),S(O)NR^(r)R^(r), S(O)₂R^(r), NR^(r)S(O)₂R^(r), NR^(r)S(O)₂NR^(r)R^(r)and S(O)₂NR^(r)R^(r), wherein the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(p) is optionallysubstituted with 1, 2 or 3 R^(q) substituents; or any two R^(a)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groupoptionally substituted with 1, 2 or 3 R^(h) substituents independentlyselected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-,C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN,OR^(i), SR^(i), NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i),OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₆₋₁₀aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3 R^(j)substituents independently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k),SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k), whereinthe C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-memberedheteroaryl, 4-6 membered heterocycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy of R^(j) are each optionallysubstituted with 1, 2 or 3 independently selected R^(q) substituents; ortwo R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S; or any two R^(c) substituents together with the nitrogen atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(e) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; or any two R^(g)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; or any two R^(k) substituents together with thenitrogen atom to which they are attached form a 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(o) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; and each R^(e),R^(i), R^(k), R^(o) or R^(p) is independently selected from H, C₁₋₄alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, 4-7membered heterocycloalkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, 4-7 membered heterocycloalkyl, C₂₋₄ alkenyl, andC₂₋₄ alkynyl of R^(e), R^(i), R^(k), R^(o) or R^(p) are each optionallysubstituted with 1, 2 or 3 R^(q) substituents; each R^(q) isindependently selected from OH, CN, —COOH, NH₂, halo, C₁₋₆ haloalkyl,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, phenyl, 5-6 memberedheteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR¹²,NR¹²R¹², and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroarylof R^(q) are each optionally substituted with halo, OH, CN, —COOH, NH₂,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyland each R¹² is independently C₁₋₆ alkyl;

is a single bond or a double bond to maintain ring A being aromatic; andwith the proviso that the compound is other than6-(6-chloro-3-methylimidazol[1,2-a]pyridine-2-yl)-4-(4-chlorophenyl)-(1,1-dimethylethoxy)-2,5-dimethyl-3-pyridineaceticacid or6-(6-chloroimidazol[1,2-a]pyridine-2-yl)-4-(4-chlorophenyl)-(1,1-dimethylethoxy)-2,5-dimethyl-3-pyridineaceticacid, or enantiomers thereof.
 2. The compound of claim 1, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein: oneof Y¹ and Y² is N and the other of Y¹ and Y² is C; X¹ is N or CR^(i); X²is N or CR²; X³ is N or CR³; X⁴ is N or CR⁴; X⁵ is N or CR⁵; X⁶ is N orCR⁶; Cy is C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5- to 14-membered heteroaryl,or 4- to 10-membered heterocycloalkyl, each of which is optionallysubstituted with 1 to 4 independently selected R⁷ substituents; Z¹ is Nor CR^(8a); Z² is N or CR^(8b); Z³ is N or CR^(8c); R¹, R², R^(8a),R^(8b) and R^(8c) are each independently selected from H, C₁₋₄ alkyl,C₃₋₄ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, CN, OH, C₁₋₄ alkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂,NHOR¹⁰, C(O)R¹⁰, C(O)NR¹⁰R¹⁰, C(O)OR¹⁰, OC(O)R¹⁰, OC(O)NR¹⁰R¹⁰,NR¹⁰C(O)R¹⁰, NR¹⁰C(O)OR¹⁰, NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰,C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰,NR¹⁰S(O)₂NR¹⁰R¹⁰, S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and S(O)₂NR¹⁰R¹⁰,wherein each R¹⁰ is independently selected from H and C₁₋₄ alkyloptionally substituted with 1 or 2 groups independently selected fromhalo, OH, CN and C₁₋₄ alkoxy; and wherein the C₁₋₄ alkyl, C₃₋₄cycloalkyl, C₂₋₄ alkenyl and C₂₋₄ alkynyl of R¹, R², R^(8a), R^(8b) andR^(8c) are each optionally substituted with 1 or 2 substituentsindependently selected from halo, OH, CN and C₁₋₄ alkoxy; R⁹ is C₁₋₄alkyl, halo, CN, OH, cyclopropyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂,NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹, C(O)OR¹¹, OC(O)R¹¹, OC(O)NR¹¹R¹¹,NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹¹, C(═NR¹¹)R¹¹,C(═NR¹¹)NR¹¹R¹¹, NR¹¹C(═NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹,NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and S(O)₂NR¹¹R¹¹,wherein C₁₋₄ alkyl, cyclopropyl, C₂₋₄ alkynyl and C₁₋₄ alkoxy of R⁹ areeach optionally substituted with 1 or 2 substituents selected from halo,OH, CN and OCH₃ and each R¹¹ is independently selected from H and C₁₋₄alkyl optionally substituted with 1 or 2 halo, OH, CN or OCH₃substituents; R³, R⁴, R⁵, R⁶ and R⁷ are each independently selected fromH, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵, R⁶ and R⁷ are eachoptionally substituted with 1, 2, 3, or 4 R^(b) substituents, with theproviso that at least one of R³, R⁴, R⁵ and R⁶ is other than H; or twoadjacent R⁷ substituents on the Cy ring, taken together with the atomsto which they are attached, form a fused phenyl ring, a fused 5-, 6- or7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroarylring or a fused C₃₋₆ cycloalkyl ring, wherein the fused 5-, 6- or7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroarylring each have 1-4 heteroatoms as ring members selected from N, O and Sand wherein the fused phenyl ring, fused 5-, 6- or 7-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(b) substituents; each R^(a) is independentlyselected from H, CN, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionallysubstituted with 1, 2, 3, 4, or 5 R^(d) substituents; each R^(d) isindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH₂, NHOR^(e), OR^(e),SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e),OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl ofR^(d) are each further optionally substituted with 1-3 independentlyselected R^(q) substituents; each R^(b) substituent is independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(C))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) andS(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each further optionallysubstituted with 1-3 independently selected R^(d) substituents; eachR^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR)NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o); each R^(g) is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionally substitutedwith 1-3 independently selected R^(p) substituents; or any two R^(a)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groupoptionally substituted with 1, 2 or 3 R^(h) substituents independentlyselected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i),NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i),and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each furtheroptionally substituted by 1, 2, or 3 R^(j) substituents independentlyselected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k); or twoR^(h) groups attached to the same carbon atom of the 4- to 10-memberedheterocycloalkyl taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkylhaving 1-2 heteroatoms as ring members selected from O, N or S; or anytwo R^(c) substituents together with the nitrogen atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 independently selected R^(h)substituents; or any two R^(e) substituents together with the nitrogenatom to which they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(g) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; or any two R^(i)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; or any two R^(o) substituents together with thenitrogen atom to which they are attached form a 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; and each R^(e), R^(i), R^(k),R^(o) or R^(p) is independently selected from H, C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₁₋₄ haloalkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl, and C₂₋₄ alkynylof R^(e), R^(i), R^(k), R^(o) or R^(p) are each optionally substitutedwith 1, 2 or 3 R^(q) substituents; each R^(q) is independently selectedfrom OH, CN, —COOH, NH₂, halo, C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, C₁₋₆ alkylthio, phenyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄haloalkoxy, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, and 5-6 membered heteroaryl of R^(q) are eachoptionally substituted with halo, OH, CN, —COOH, NH₂, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl and 4-6 memberedheterocycloalkyl and each R¹² is independently C₁₋₆ alkyl; and

is a single bond or a double bond to maintain ring A being aromatic. 3.The compound of claim 1 or 2, having Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: one of Y¹ and Y² is N and the other of Y¹ and Y² is C; X¹ is Nor CR¹; X² is N or CR²; X³ is N or CR³; X⁴ is N or CR⁴; X⁵ is N or CR⁵;X⁶ is N or CR⁶; R¹, R² and R⁸ are each independently selected from H,C₁₋₄ alkyl, C₃₋₄ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, CN, OH,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl,—N(C₁₋₄ alkyl)₂, NHOR¹⁰, C(O)R¹⁰, C(O)NR¹⁰R¹⁰, C(O)OR¹⁰, OC(O)R¹⁰,OC(O)NR¹⁰R¹⁰, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)OR¹⁰, NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰,C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰,NR¹⁰S(O)₂NR¹⁰R¹⁰, S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and S(O)₂NR¹⁰R¹⁰,wherein each R¹⁰ is independently selected from H and C₁₋₄ alkyloptionally substituted with 1 or 2 groups independently selected fromhalo, OH, CN and C₁₋₄ alkoxy; and wherein the C₁₋₄ alkyl, C₃₋₄cycloalkyl, C₂₋₄ alkenyl and C₂₋₄ alkynyl of R¹, R² or R⁸ are eachoptionally substituted with 1 or 2 substituents independently selectedfrom halo, OH, CN and C₁₋₄ alkoxy; R⁹ is C₁₋₄ alkyl, halo, CN, OH,cyclopropyl, C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,NH₂, —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹,C(O)OR¹¹, OC(O)R¹¹, OC(O)NR¹¹R¹¹, NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹,NR¹¹C(O)NR¹¹R¹¹, C(═NR¹¹)R¹¹, C(═NR¹¹)NR¹¹R¹¹, NR¹¹C(═NR¹¹)NR¹¹R¹¹,NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹, NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹,S(O)₂R¹¹, and S(O)₂NR¹¹R¹¹, wherein each R¹¹ is independently selectedfrom H and C₁₋₄ alkyl optionally substituted with 1 or 2 halo, OH, CN orOCH₃; R³, R⁴, R⁵, R⁶ and R⁷ are each independently selected from H,halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R³, R⁴, R⁵, R⁶ and R⁷ are eachoptionally substituted with 1, 2, 3, or 4 R^(b) substituents, with theproviso that at least one of R³, R⁴, R⁵ and R⁶ is other than H; or twoadjacent R⁷ substituents on the phenyl ring, taken together with thecarbon atoms to which they are attached, form a fused phenyl ring, afused 5-, 6- or 7-membered heterocycloalkyl ring, a fused 5- or6-membered heteroaryl ring or a fused C₅₋₆ cycloalkyl ring, wherein thefused 5-, 6- or 7-membered heterocycloalkyl ring and fused 5- or6-membered heteroaryl ring each have 1-4 heteroatoms as ring membersselected from N, O and S and wherein the fused phenyl ring, fused 5-, 6-or 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroarylring and fused C₅₋₆ cycloalkyl ring are each optionally substituted with1 or 2 independently selected R^(q) substituents; each R^(a) isindependently selected from H, CN, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents;each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH₂,NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl ofR^(d) are each further optionally substituted with 1-3 independentlyselected R^(q) substituents; each R^(b) substituent is independentlyselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c), OR^(c),SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) andS(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each further optionallysubstituted with 1-3 independently selected R^(d) substituents; eachR^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR)NR^(o)R^(o), NR^(o)C(═NR)NR^(o)R^(o), S(O)R^(o),S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o), NR^(o)S(O)₂NR^(o)R^(o),and S(O)₂NR^(o)R^(o); each R^(g) is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionally substitutedwith 1-3 independently selected R^(p) substituents; or any two R^(a)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groupoptionally substituted with 1, 2 or 3 R^(h) substituents independentlyselected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i),NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i),and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each furtheroptionally substituted by 1, 2, or 3 R^(j) substituents independentlyselected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN,NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k),OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k); or twoR^(h) groups attached to the same carbon atom of the 4- to 10-memberedheterocycloalkyl taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkylhaving 1-2 heteroatoms as ring members selected from O, N or S; or anytwo R^(c) substituents together with the nitrogen atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 independently selected R^(h)substituents; or any two R^(e) substituents together with the nitrogenatom to which they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(g) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; or any two R^(i)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; or any two R^(o) substituents together with thenitrogen atom to which they are attached form a 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; and each R^(e), R^(i), R^(k),R^(o) or R^(p) is independently selected from H, C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₁₋₄ haloalkyl, C₂₋₄alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl, and C₂₋₄ alkynylof R^(e), R^(i), R^(k), R^(o) or R^(p) are each optionally substitutedwith 1, 2 or 3 R^(q) substituents; each R^(q) is independently selectedfrom OH, CN, —COOH, NH₂, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio,phenyl, 5-6 membered heteroaryl, C₃₋₆ cycloalkyl, NHR¹², NR¹²R¹², andC₁₋₄ haloalkoxy, wherein the C₁₋₄ alkyl, phenyl and 5-6 memberedheteroaryl of R^(q) are each optionally substituted with OH, CN, —COOH,NH₂, C₁₋₄ alkoxy, C₃₋₁₀ cycloalkyl and 4-6 membered heterocycloalkyl andeach R¹² is independently C₁₋₆ alkyl;

is a single bond or a double bond to maintain ring A being aromatic; thesubscript n is an integer of 1, 2, 3, 4 or 5; and the subscript m is aninteger of 1, 2 or
 3. 4. The compound of any one of claims 1-3, havingFormula (II):

wherein R⁴ is halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R⁴ are each optionallysubstituted with 1, 2, 3, or 4 R^(b) substituents, or a pharmaceuticallyacceptable salt or a stereoisomer thereof.
 5. The compound of any one ofclaims 1-4, having Formula (III):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 6. Thecompound of any one of claims 1-5, having Formula (IV):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 7. Thecompound of any one of claims 1-4, having Formula (V):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 8. Thecompound of any one of claims 1-4, having Formula (VI):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 9. Thecompound of any one of claims 1-8, or a pharmaceutically acceptable saltor a stereoisomer thereof, wherein the moiety:

is selected from:


10. The compound of any one of claims 1-9, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein R¹, R², R³ and R⁵ areeach H.
 11. The compound of any one of claims 1-8, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein X¹ is N, X² is CH,X³, X⁵ and X⁶ are each CH, Y¹ is N and Y² is C.
 12. The compound of anyone of claims 1-8, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein X¹ is CH, X² is CH, X³, X⁵ and X⁶ are eachCH, Y¹ is C and Y² is N.
 13. The compound of any one of claims 1-8, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein X¹is CH, X² is CH, X³ and X⁶ are each CH, X⁵ is N, Y¹ is C and Y² is N.14. The compound of any one of claims 1-8, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein X¹ is N, X² is CH, X³and X⁶ are each N, X⁵ is CH, Y¹ is N and Y² is C.
 15. The compound ofany one of claims 1-8, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein X¹ is N, X² is CH, X³ and X⁵ are each CH,X⁶ is N, Y¹ is N and Y² is C.
 16. The compound of any one of claims 1-8,or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinX¹ is N, X² is CH, X³ and X⁶ are each CH, X⁵ is N, Y¹ is N and Y² is C.17. The compound of any one of claims 1-8, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein X¹ is N, X² is CH, X⁵and X⁶ are each CH, X³ is N, Y¹ is N and Y² is C.
 18. The compound ofany one of claims 1-8, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein X¹ and X² are each N, X³, X⁵ and X⁶ areeach CH, Y¹ is C and Y² is N.
 19. The compound of any one of claims 1-8,or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinX¹ and X² are each N, X³ is CH, X⁵ is N, X⁶ is CR⁶, Y¹ is C and Y² is N.20. The compound of any one of claims 1-8, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein X¹ is N, X² is CH, X³and X⁵ are each CH, X⁶ is CR⁶, Y¹ is N and Y² is C.
 21. The compound ofany one of claims 1-8, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein X¹ and X² are each N, X³ and X⁵ are eachCH, X⁶ is CR⁶, Y¹ is N and Y² is C.
 22. The compound of any one ofclaims 1-21, or a pharmaceutically acceptable salt or a stereoisomerthereof, wherein R⁴ is —CH₂—R^(b).
 23. The compound of claim 22, or apharmaceutically acceptable salt or a stereoisomer thereof, whereinR^(b) is —NR^(c)R^(c).
 24. The compound of any of claims 1-23, or apharmaceutically acceptable salt or a stereoisomer thereof, wherein R⁴is 2-hydroxyethylaminomethyl, 2-hydroxyethyl(methyl)aminomethyl,2-carboxypiperidin-1-ylmethyl, (cyanomethyl)aminomethyl,(S)-2-carboxypiperidin-1-ylmethyl or (R)-2-carboxypiperidin-1-ylmethyl.25. The compound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein the compound is selected from:2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl]methyl}amino)ethanol;2-({[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}amino)ethanol; (2S)-1-{[2-(2-methylbiphenyl-3-yl)indolizin-7-yl]methyl}piperidine-2-carboxylicacid;(2S)-1-{[6-(2-methylbiphenyl-3-yl)pyrrolo[1,2-c]pyrimidin-3-yl]methyl}piperidine-2-carboxylicacid;2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamino)ethanol;2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamino)acetonitrile;2-((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methylamino)acetamide;2-(methyl((6-(2-methylbiphenyl-3-yl)imidazo[1,2-b][1,2,4]triazin-2-yl)methyl)amino)ethanol;2-((8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylamino)ethanol;(S)-1-((8-methyl-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methyl)piperidine-2-carboxylicacid;2-((8-chloro-2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyridin-6-yl)methylamino)ethanol;2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrimidin-6-yl]methyl}amino)ethanol;2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazin-6-yl]methyl}amino)ethanol;(S)-1-((2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl)methyl)piperidine-2-carboxylicacid;2-({[2-(2-methylbiphenyl-3-yl)imidazo[1,2-b]pyridazin-6-yl]methyl}amino)ethanol;2-({[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl}amino)ethanol;(2S)-1-{[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl}piperidine-2-carboxylic acid;2-({[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol;(2S)-1-{[2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}piperidine-2-carboxylic acid;and2-({[5-methyl-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-c]pyrimidin-7-yl]methyl}amino)ethanol.26. The compound of claim 1, or a pharmaceutically acceptable salt or astereoisomer thereof, wherein the compound is selected from:2-({[8-chloro-2-(2-methylbiphenyl-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol;2-({[8-[(2-methoxyethyl)amino]-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl}amino)ethanol;4-[6-{[(2-hydroxyethyl)amino]methyl}-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-8-yl]butanenitrile;[6-{[(2-hydroxyethyl)amino]methyl}-2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyridin-8-yl]acetonitrile;2-(8-chloro-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile;2-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile;and2-(8-(cyanomethyl)-6-{[(2-hydroxyethyl)amino]methyl}[1,2,4]triazolo[1,5-a]pyridin-2-yl)-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile.27. A pharmaceutical composition comprising a compound of any one ofclaims 1-26, or a pharmaceutically acceptable salt or a stereoisomerthereof.
 28. A method of inhibiting PD-1/PD-L1 interaction, said methodcomprising administering to an individual a compound of any one ofclaims 1-26, or a pharmaceutically acceptable salt or a stereoisomerthereof.
 29. A method of treating a disease or disorder associated withinhibition of PD-1/PD-L1 interaction, said method comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of any one of claims 1-26, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, or a composition of claim 27.30. The method of claim 29, wherein the disease or disorder is a viralinfection or cancer.